ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

Wednesday, October 3, 2001

8:40 a.m.

The Town Center Hotel

8727 Colesville Road

Maryland Ballroom

Silver Spring, Maryland

PARTICIPANTS

Roy M. Gulick, M.D., M.P.H., Chair

Tara P. Turner, Pharm.D., Executive Secretary

Members

John D. Hamilton, M.D.

Princy N. Kumar, M.D.

Roger J. Pomerantz, M.D.

Sharilyn K. Stanley, M.D.

Brian Wong, M.D.

Ram Yogev, M.D.

Consultants (voting) Pending New AVAC Members

Victor G. DeGruttola, Sc.D.

Janet A. Englund, M.D.

Jonathan M. Schapiro, M.D.

Lauren V. Wood, M.D.

Consultants (voting)

Henry G. Bone III, M.D.

Barbara P. Lukert, M.D. (by telephone)

Patient Representative (non-voting)

Robert J. Munk, Ph.D.

Industry Representative (non-voting)

Eugene Sun, M.D.

Guests (non-voting)

David Dorsky, M.D., Ph.D.

Victoria A. Johnson, M.D.

Pablo Tebas, M.D.

FDA

Debra Birnkrant, M.D.

James Farrelly, Ph.D.

Mark Goldberger, M.D., M.P.H.

Jeffrey Murray, M.D., M.P.H.

Bruce Schneider, M.D.

Kimberly Struble, Pharm.D.

C O N T E N T S

Call to Order:

Roy M. Gulick, M.D., M.P.H. 4

Conflict of Interest Statement:

Tara P. Turner, Pharm.D. 6

Introduction/Opening Remarks:

Debra Birnkrant, M.D. 9

Overview of Development Program:

Norbert Bischofberger, Ph.D. 17

Clinical Trial Results:

Jay Toole, M.D., Ph.D. 24

Phase IV Plans and Concluding Remarks:

Norbert Bischofberger, Ph.D. 44

Kimberly Struble, Pharm.D. 50

James Farrelly, Ph.D. 63

Kimberly Struble, Pharm.D. 69

Questions to Presenters 78

Open Public Hearing 145

Yvette Delph, M.D.

Treatment Action Group, TAG

Brett Grodeck 153

Santa Monica, California

Ben Cheng (read by Dr. Delph) 163

Project Inform

Jules Levin 167

National AIDS Treatment

Advocacy Project, NATAP

Questions to Committee 172

Committee Discussion 175

P R O C E E D I N G S

DR. GULICK: Good morning. I am Trip Gulick from Cornell. I would like to welcome you to this meeting of the Antiviral Advisory Committee.

I would like to start by having the members sitting around the table introduce themselves. Let's start with Dr. Sun. Please state your name and your affiliation.

DR. SUN: Eugene Sun, Abbott Laboratories.

DR. MUNK: Bob Munk, New Mexico AIDS InfoNet.

DR. TEBAS: Pablo Tebas, Washington University in St. Louis.

DR. JOHNSON: Vicki Johnson, University of Alabama at Birmingham.

DR. DORSKY: David Dorsky, University of Connecticut.

DR. POMERANTZ: Roger Pomerantz, Thomas Jefferson University, Philadelphia.

DR. BONE: Henry Bone, Michigan Bone and Mineral Clinic, Detroit.

DR. STANLEY: Sharilyn Stanley, Texas Department of Health.

DR. YOGEV: Ram Yogev, Children's Memorial Hospital, Chicago.

DR. HAMILTON: John Hamilton, Duke University and Durham VA Medical Center.

DR. KUMAR: Princy Kumar, Georgetown University, Washington, D.C.

DR. TURNER: Tara Turner, Executive Secretary for the Committee.

DR. SCHAPIRO: Jonathan Schapiro, Stanford and Tel Aviv Universities.

DR. WONG: Brian Wong of the Westhaven V.A. and Yale University.

DR. DeGRUTTOLA: Victor DeGruttola, Harvard School of Public Health.

DR. ENGLUND: Janet Englund, Department of Pediatrics, University of Chicago.

DR. FARRELLY: Jim Farrelly, Pharmacology, FDA.

DR. SCHNEIDER: Bruce Schneider, Division of Metabolic and Endocrine Drug Products, FDA.

DR. STRUBLE: Kim Struble, FDA.

DR. MURRAY: Jeff Murray, FDA.

DR. BIRNKRANT: Debra Birnkrant, FDA.

DR. GOLDBERGER: Mark Goldberger, FDA.

DR. GULICK: Thank you. We also have Dr. Lukert who was unable to attend but is going to be joining us by videoconference. I am not sure if she is actually hooked in or can hear us. We are assuming that she will be patched in at some point and when she is, we will stop and introduce her also.

I would like Tara Turner now to read the conflict of interest statement.

DR. TURNER: Thank you.

The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.

Based on the submitted agenda for the meeting and all financial interests reported by the Committee participants, it has been determined that all interests in firms regulated by the Center for Drug Evaluation and Research which have been reported by the participants present no potential for an appearance of a conflict of interest at this meeting with the following exceptions.

In accordance with 18 U.S.C. 208(b)(3), full waivers have been granted to Dr. Roy Gulick, Dr. John Hamilton, Dr. Princy Kumar, Dr. Henry Bone, Dr. Janet Englund, and Dr. Jonathan Schapiro.

A copy of these waiver statements may be obtained by submitting a written request to the Agency's Freedom of Information Office, Room 12A-30 of the Parklawn Building.

Further, in accordance with 21 U.S.C. 355(n)(4), Dr. John Hamilton and Dr. Princy Kumar have been granted waivers that permit them to vote on matters related to today's discussions.

We would like to disclose for the record that Dr. Princy Kumar, Dr. Roger Pomerantz, Dr. Victor DeGruttola, and Dr. Jonathan Schapiro have interests which do not constitute financial interests within the meaning of 18 U.S.C. 208(a), but which could create the appearance of a conflict.

The Agency has determined, notwithstanding these interests, that the interest of the Government in their participation outweighs the concern that the integrity of the Agency's programs may be questioned. Therefore, Drs. Kumar, Pomerantz, DeGruttola, and Schapiro may participate fully in today's discussion and vote concerning Viread.

With respect to FDA's invited guest speakers, Drs. Victoria Johnson, Robert Munk, and Pablo Tebas have reported interests which we believe should be made public to allow the participants to objectively evaluate their comments.

Dr. Johnson would like to disclose that she has work on grants supported by GlaxoSmithKline and Bristol- Myers Squibb and is a medical consultant for GlaxoSmithKline and Bristol-Myers Squibb regarding HIV drug resistance. She has also received honoraria from Roche, Bristol-Myers Squibb, GlaxoSmithKline speakers bureaus.

Dr. Munk would like to disclose that he receives speaker fees from GlaxoSmithKline.

Dr. Tebas would like to disclose that he has been a local investigator in multi-center trials sponsored by GlaxoSmithKline and Bristol-Myers Squibb. He also believes that he once attended a GlaxoSmithKline advisory meeting.

In addition, we would like to note that Dr. Eugene Sun is participating in this meeting as an industry representative, acting on behalf of regulated industry. As such, he has not been screened for any conflicts of interest.

In the event that the 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 firm whose products they may wish to comment upon.

Thank you.

DR. GULICK: Thanks very much.

I would like to call on Dr. Debra Birnkrant to give the introduction from the FDA.

DR. BIRNKRANT: Good morning. I would really like to welcome everyone to today's advisory committee meeting on tenofovir DF, and I really mean that from my heart, because I know it was very difficult for a lot of you to travel to get here and we really appreciate all of your efforts.

I would also like to mention that in addition to our expert panel members, we have invited guests who are experts in the areas of HIV resistance and in bone metabolism, but before we get to today's scientific discussion, I would like to acknowledge three advisory committee members who are rotating off our committee.

They are Drs. Yogev, Pomerantz, and Hamilton, and we have certificates for your distinguished service.

Dr. Yogev is from Children's Memorial Hospital in Chicago, and he has served on our committee since 1997. We would like to thank him for all of his efforts and help during our deliberations. We have a certificate for him today. Why don't you come up and get your certificate, and you will be receiving a wooden plaque in the near future. Thank you very much.

[Applause.]

DR. BIRNKRANT: Dr. John Hamilton is from the Durham VA and from Duke University Medical Center. He has also served on our committee for the last four years, and we would like to thank him for his exemplary service.

[Applause.]

DR. BIRNKRANT: Dr. Pomerantz from Thomas Jefferson University Hospital where I used to be a volunteer many years ago. We would like to thank him for his service, as well, and for helping us out during our last advisory committee meeting where he chaired the Valgan meeting.

[Applause.]

DR. BIRNKRANT: In addition, I would also like to acknowledge some of the new members who will be joining our committee as of November 1st. They are Dr. Victor DeGruttola from the Harvard School of Public Health, Dr. Janet Englund from the University of Chicago, Dr. Jonathan Schapiro from Stanford University, and Dr. Lauren Wood from NIH.

[Slide.]

Turning to today's discussion, as outlined in the background document received by the advisory committee members, we are convening this meeting today to discuss four key issues in the tenofovir DF NDA.

They are the treatment indication, the nonclinical and clinical assessment of the effects of tenofovir DF on bone, the resistance data contained in the NDA package, and the design of trials for traditional approval.

[Slide.]

The first issue I would like to elaborate on is the treatment indication. Gilead proposes the following treatment indication: Viread, in combination with other antiretroviral agents, is indicated for the treatment of HIV-infected adults.

This indication is based on analyses of plasma RNA and CD4 counts in two controlled trials in treatment- experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy. At present, there are no results from controlled trials evaluating the effect of tenofovir on clinical progression of HIV.

[Slide.]

This treatment indication is based on pivotal studies 902 and 907 which are contained in the NDA and were conducted in a treatment-experienced adult population. These trials were both designed as intensification strategies where either tenofovir or placebo were added to a stable antiretroviral regimen.

The treatment-experienced patients in these trials had a median duration of therapy of approximately 4 to 5 years. The mean baseline load was approximately 3.4 logs or 2,300 copies.

Mean baseline CD4 counts were 410 cells, and participants in these trials had baseline mutations to all antiretroviral classes.

We will be requesting the advisory committee's input this morning and this afternoon regarding the labeled indication, that is, should it be broad as proposed by Gilead and as found in other labels of antiretroviral agents, or should it be limited to a treatment-experienced population.

[Slide.]

The next issue we would like to bring before you today has to do with the effects of tenofovir DF on bone, and the reason we are bringing this forward today is that bone mineral density reductions were seen, as well as osteomalacia, in multiple species in preclinical trials.

The mechanism is not fully defined, and you will hear more about the mechanism later today.

The clinical trial data were also limited for bone mineral density, so therefore, we will be seeking your advice regarding the implications of both the nonclinical and clinical data contained in the NDA, as well as recommendations for additional studies after you review the presentations regarding the extensive work that Gilead has done with regard to preclinical testing and evaluation of the bone effects, as well as the clinical testing that is being conducted in Study 903. We will also ask you to comment on the monitoring plans and the clinical study.

[Slide.]

With regard to the virology data, the Viread NDA contains more virology data than any other NDA we have brought to this committee. There were many prospective and exploratory analyses conducted that evaluated the HIV RNA response by baseline phenotype and genotype, as well as number and type of thymidine analogue mutations at baseline. Therefore, we will be seeking your comments on the types of resistance analyses that were presented in the NDA, which ones should be used for future drug development and which ones should appear in the product labeling.

[Slide.]

Lastly, I would like to bring to your attention that we will be asking for your input with regard to the design of the traditional approval study, but I need to put that into the perspective of the accelerated approval regulations.

The Viread NDA was submitted in May of 2001 under the accelerated approval regulations, which allow for acceleration of approval of drugs for patients who have serious and life-threatening conditions, such as HIV, if they provide meaningful therapeutic benefit over existing therapies.

I would like to pause and commend Gilead at this point for studying Viread in the treatment-experienced population, a population with limited therapeutic options. This is definitely in keeping with the spirit of the accelerated approval regulations.

Under accelerated approval, a drug must have an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint other than survival or irreversible morbidity.

To that end, the Division of Antiviral Drug Products requires two adequate and well-controlled trials, such as 902 and 907, of 24 weeks duration to support accelerated approval, but in order for a product that is approved under the accelerated approval regulations to continue to be marketed, it must be subject to the need to confirm those findings found in the 24-week trials to establish clinical benefit.

The way that we look at the durability of the benefit is that we require two studies to confirm the findings in the 24-week trials. That is, we require two studies of 48 weeks duration to support traditional approval.

[Slide.]

To date, Gilead has put forth Study 903, which is being conducted actually in naive subjects, and this trial is fully enrolled. It compares tenofovir DF to stavudine on a background of lamivudine and efavirenz.

I will mention here that the confirmatory traditional approval trials do not necessarily need to replicate the findings in the accelerated approval trials in the same populations. That is, for traditional approval, it is acceptable to have studies either in pediatrics or in a naive population if the accelerated approval was for a treatment-experienced population.

So, we will be seeking your advice regarding the design of the second traditional approval trial that Gilead has proposed, and this is in a pediatrics population.

[Slide.]

Lastly, I would just like to comment on today's agenda. Gilead will present first, and then the FDA will follow without a break for questions until after our break this morning, so that there is a continuity this morning.

Then, after the open public hearing, we will continue discussions and then pose the questions to the committee.

Thank you very much.

DR. GULICK: Thanks, Dr. Birnkrant.

I would like to turn now to the sponsor, Gilead Sciences, and their presentation.

Dr. Norbert Bischofberger will start.

DR. BISCHOFBERGER: Good morning. My name is Norbert Bischofberger from Gilead Sciences. We are going to review the New Drug Application for tenofovir disoproxil fumarate.

[Slide.]

Joining us today are three consultants - Dr. Harry Genant from University of California at San Francisco, Dr. Jip Schooley, University of Colorado Health Sciences Center, and Dr. Steve Teitelbaum, Washington University in St. Louis.

Due to an injury accident, unfortunately, Dr. Genant can't be physically with us today. He underwent surgery on Monday, but he is doing well and he is joining us by phone.

[Slide.]

In today's presentation, I will first review the preclinical data and the clinical development program. Dr. Jay Toole will then present to you efficacy, safety, and clinical virology data from our clinical studies. I will finish up our presentation with some concluding remarks.

[Slide.]

Despite the availability of a number of antiretrovirals today, there still exists a tremendous unmet medical need. When trying to construct a viable treatment regimen, both patient and their physicians face the challenge of drug resistance, pill burden, drug interactions, tolerability, and durability of treatment response.

Tenofovir disoproxil fumarate is a novel antiretroviral which addresses many of these challenges. Tenofovir disoproxil fumarate, or tenofovir DF, is an orally bioavailable prodrug of tenofovir. Tenofovir contains a phosphomate.

It is an analogue of deoxyadenosinemonophosphate and as such, it is a nucleotide reverse transcriptase inhibitor. Tenofovir is dosed as one tablet, once daily, and it has a unique resistance profile showing durable activity against otherwise resistant viruses. This unique resistance profile is evident from in vitro cross-resistance studies.

[Slide.]

In vitro tenofovir retains activity against recombinant viruses expressing mutations at positions 67, 70, and 215, which are zidovudine resistant viruses. It also retains activity against recombinant viruses expressed in the L74V mutation, which are ddI resistant, against T69D, which are ddC resistant, and against Q151M complex, which are multinucleoside-resistant viruses.

Increased activity in vitro is observed against viruses expressing M184V or the 3TC resistance mutation.

From in vitro selection experiments, viruses expressing K65R emerged, and those viruses show a 3- to 4-fold reduced susceptibility to tenofovir.

[Slide.]

This unique resistance profile against recombinant viruses was confirmed when tenofovir was evaluated against HIV clinical isolates. Again, what was found is that 3TC resistant viruses with the M184V, ddI resistant viruses with L74V, and abacavir-resistant viruses expressing mutations at positions 74, 115, and 184 were slightly hypersusceptible to tenofovir with a mean 0.6- to 0.7-fold change from wild-type susceptibility.

Multinucleoside resistant viruses with Q151M or viruses expressing the tenofovir-associated resistance mutation K65R in general fell within the normal susceptibility range, which is less than 3-fold change from wild-type susceptibility.

High-level zidovudine resistant viruses, which express T215Y, in combination with other thymidine analogue mutations or TAMs, were either within the normal or the intermediate susceptibility range, which is less than 10-fold change from wild-type.

Finally, viruses expressed in the uncommon T69 insertion mutation were either within the normal intermediate or resistant susceptibility range, and showed a mean 12-fold change from wild-type susceptibility.

[Slide.]

Tenofovir is administered as one tablet, once daily. Once-daily dosing is supported by the long intracellular half-life of tenofovir in human PBMCs, which is 10 hours in activated cells and 50 hours in resting cells. Once-daily dosing is also supported by the terminal pharmacokinetic serum half-life in humans, which is 17 hours.

Preclinical experiments showed that tenofovir is not a substrate or an inhibitor or an inducer of cytochrome p450, suggesting that it has a low potential to cause drug interactions with compounds undergoing hepatic metabolism.

This was indeed shown in Study 909, which found no clinically significant drug interactions of tenofovir DF with the NNRTI efavirenz or the PIs indinavir or lopinavir or ritonavir.

Tenofovir is renally cleared in a combination of filtration and tubular secretion. Study 909 also evaluated two nucleosides, 3TC and ddI, which undergo renal secretion, and the study found that co-administration of tenofovir DF with either 3TC or ddI did not affect clearance.

Finally, the oral bioavailability of tenofovir DF in humans ranges from 25 percent in the fasted state to 39 percent in the fed state.

[Slide.]

In vitro data from enzyme inhibition experiments or in tissue culture show that tenofovir does not affect mitochondrial DNA synthesis, mitochondrial DNA content, or lactic acid production, suggesting that there is a low potential for tenofovir to cause mitochondrial toxicity.

Toxicology studies in animals, which were designed to identify potential target organs in humans, suggested that GI, the kidney, and the bone as three such organs. The GI effect of tenofovir DF was a local, high-dose effect observed only in rats. These animals were administered a high dose of tenofovir, 1,000 mg/kg, in order to overcome the relatively low oral bioavailability in that species.

Nephrotoxicity was observed in dogs and monkeys, and it was characterized predominantly histologically by proximal renal tubular changes.

Finally, bone effects were observed in rats, dogs, and monkeys. The most significant effects of tenofovir on bone were observed in juvenile monkeys which were administered a dose of tenofovir subcutaneously, which correlates to about 12- to 25-fold the human exposure.

These animals developed nephrotoxicity associated with bone abnormalities characterized histologically as osteomalacia. These bone abnormalities were reversible when either dosing was reduced or dosing was discontinued, and when these animals were started at the lower dose, correlating to about 4-fold the human exposure, and dosed up to three years, there was no radiographic evidence of any bone abnormalities.

Having identified the kidney and the bone as two potential target organs in humans, we instituted appropriate monitoring in all our clinical studies. As you will hear in the subsequent presentation by Dr. Jay Toole, there is currently no evidence of tenofovir DF-related, clinically significant nephrotoxicity or bone abnormalities in our clinical studies.

[Slide.]

Our safety database that was submitted with the NDA consisted of almost 1,000 HIV-infected patients who had received tenofovir DF 300 mg. At the time of the NDA submission, which was May 1, 2001, we had data on approximately 150 patients who had received tenofovir DF 300 mg for at least 48 weeks.

At the time of the safety update, which was August 15, 2001, we had data on more than 600 patients who had received tenofovir DF 300 mg for at least 48 weeks.

I would now like to ask for Dr. Jay Toole to present to you the efficacy, safety, and clinical virology data from our clinical studies.

DR. TOOLE: Good morning. My name is Jay Toole. I will present the clinical trial results of tenofovir.

[Slide.]

We conducted three placebo-controlled studies. Study 901 evaluated tenofovir, short-term monotherapy, at four dose levels. Studies 902 and 907 were longer duration intensification studies in which tenofovir or placebo were added to existing background regimens.

We chose the intensification design because it allowed for the clearest demonstration of the impact of a single agent in combination regimens.

Study 902 evaluated three dose levels, and Study 907, our Phase III study, evaluated the 300 mg dose for which we seek approval.

I will also present data for renal and bone parameters and from our clinical virology studies.

DR. GULICK: Dr. Toole, can I just stop you for a second.

[Interruption.]

[Recess,]

DR. GULICK: Welcome back. We are going to try to go on with the presentations this morning. After lunch, we are actually going to go to another room.

With apologies to our sponsor and thanks for their good humor throughout this, let's resume.

DR. TOOLE: If I could have the next slide, please.

[Slide.]

We will begin with Study 901, which was a randomized, double-blind, placebo-controlled, dose-escalation study of tenofovir monotherapy.

There were four dose levels studied ranging from 75 to 600 mg/day.

To enroll, patients had to have HIV RNA greater than 10,000 copies/mL, and CD4 counts greater than 200.

There were 10 patients enrolled per dose level, 8 assigned to tenofovir and 2 to placebo.

A single dose was administered on day 1 for pharmacokinetic sampling. Then, after one week, 28 consecutive days of tenofovir administration. Both treatment-naive and experienced patients were enrolled in the study with the following baseline characteristics.

[Slide.]

Mean CD4 counts of 346 and 391, mean HIV RNA of 115,000 and 85,000; 36 percent of the patients in the placebo arm had prior treatment experience compared to 68 percent of patients in the tenofovir arm.

[Slide.]

Significant activity was observed, at the mean change from baseline to day 35, showed little change in the placebo group, a dose response with maximal activity observed in the 300 mg treatment group in which a 1.2 log reduction from baseline was observed.

Each of the treatment groups were statistically significantly different when compared with placebo, with p-values of less than 0.003. Dosing was discontinued on day 35.

[Slide.]

Following discontinuation, there was a slow return towards baseline. One week after dosing was discontinued, the 300 and 600 mg dose groups remained more than one-half log below baseline. This is consistent with a long intercellular half-life of the active moiety of tenofovir.

[Slide.]

To confirm the efficacy data in a larger number of patients, and to examine the long-term safety profile, we next conducted Study 902.

This was a randomized, double-blind, placebo-controlled study of tenofovir or placebo added to existing background regimens.

To enroll, patients had to have been on a stable background regimen for at least 8 weeks consisting of up to four approved antiretroviral agents.

Also, patients had to have HIV RNA greater than 400 and up to 100,000 copies/mL.

The primary efficacy endpoint was the time-weighted average change from baseline to week 24, also called DAVG24.

[Slide.]

Patients were randomized to one of three tenofovir dose groups or placebo in a 2:2:2:1 ratio. The double-blind phase was for 48 weeks, and after 24 weeks, patients randomized to placebo crossed over to 300 mg in a blinded fashion. After 48 weeks, all patients received 300 mg in an open label fashion for an indefinite period.

[Slide.]

186 patients were randomized and received tenofovir with the following baseline characteristics. Mean CD4 counts of 374 and a median HIV RNA of about 5,000/mL.

These patients were highly treatment experienced with a mean prior antiretroviral use of 4.6 years. Baseline genotyping was performed in this study, and identified resistance mutations associated with non-nucleosides in 32 percent of patients, protease inhibitors in 57 percent, and nucleosides in 94 percent of patients.

[Slide.]

Tenofovir was well tolerated. Disposition of patients from zero to 24 weeks shows that 25 percent of patients discontinued study in the placebo arm compared to 9 to 16 percent of patients in the tenofovir arm.

Four percent of patients discontinued for an adverse event in the placebo arm compared to 4 to 10 percent of patients in the tenofovir groups.

There was one death in the study on the 75 mg dose group of tenofovir, and this was not attributed to tenofovir by the investigator.

[Slide.]

The disposition from zero to 48 weeks, which is the end of the double-blind phase, shows about 25 percent of the patients had discontinued the study, and importantly, the percentage of patients discontinued for an adverse event remained low, at about 10 percent, and was similar among the treatment groups.

[Slide.]

The primary efficacy endpoint was achieved as the mean DAVG24 showed little change in the placebo, and tenofovir at 300 mg resulted in a 0.58 log reduction from baseline.

About 30 percent of the patients in each of the treatment arms changed their background regimen during the first 24 weeks of the study. To preclude the possible effect this would have on efficacy, on the efficacy outcome, we also conducted an analysis in the as-treated population for whom data were excluded following the period of change in the background regimen or study drug discontinuation.

The analysis of the as-treated population shows the 300 mg dose group at a 0.52 log reduction, and that remained statistically significant.

[Slide.]

The changes at week 24 appeared durable as the mean change from baseline in the 300 mg dose group at week 24 was approximately 0.6 logs below baseline, and that was durable out through week 48.

[Slide.]

There were no significant changes in CD4 cell counts at week 24, and at week 48, the changes in CD4 cell counts remained modest.

The safety profile of tenofovir was favorable.

[Slide.]

As the percent of patients with Grade 3 or 4 adverse events was 14 percent of patients in the placebo group compared to 17 to 19 percent of patients in the tenofovir arms.

These are the adverse events which occurred at least 1 percent of patients and shows a generally similar profile between tenofovir and placebo. Through 48 weeks, there was no change in the profile and no adverse event appeared dose related.

[Slide.]

Grade 3 or higher laboratory abnormalities were more common in all the dose groups, occurring in 32 percent of patients in the placebo arm compared to 30 to 34 percent of patients in the tenofovir arms.

These are the laboratory abnormalities which occurred at least 1 percent of the patients and show a generally similar profile between tenofovir and placebo. Again, through 48 weeks, there was no change in the profile and no laboratory abnormality appeared dose related.

[Slide.]

Based on the safety and efficacy results in this study, we evaluated the 300 mg dose in Study 907, our Phase III study. This was a randomized, double-blind, placebo-controlled study of tenofovir or placebo added to existing background regimens.

Similar to Study 902, to enroll, patients had to have been on a stable background regimen for at least 8 weeks consisting of up to 4 approved antiretroviral drugs.

Unlike Study 902, however, we attempted to minimize the amount of background switching or restricting the upper limit of baseline viral load to 10,000 copies/mL. This was successful in that only about 10 percent of patients in either treatment arm changed their background regimen during the first 24 weeks of this study compared to 30 percent of patients in Study 902.

The primary efficacy endpoint was DAVG24.

[Slide.]

Patients were randomized to tenofovir or placebo in a 2:1 ratio, and the double-blind phase was for 24 weeks, after which all patients received 300 mg in an open label fashion for an indefinite period.

[Slide.]

550 patients were randomized and received drug. At baseline, their characteristics were well matched with a mean age of about 40, about 15 percent of patients were female, and about 30 percent of patients were non-Caucasian.

Patients were also well matched with regard to whether their baseline, antiretroviral regimen contained either a protease inhibitor or a non-nucleoside.

[Slide.]

HIV characteristics were also well matched with median HIV RNA of about 2,300 copies and mean CD4 cell counts over 400. These patients were also highly treatment experienced with a mean prior antiretroviral use of approximately 5.5 years.

[Slide.]

A prospective virology substudy was performed in about half of the patients and identified baseline resistance mutations associated with non-nucleosides in about 50 percent of patients, protease inhibitors in about 60 percent, and nucleosides in 94 percent of patients.

[Slide.]

Tenofovir was well tolerated. Percentage of patients discontinuing through week 24 was 6 percent in both the placebo and the tenofovir arms. The percentage of patients who discontinued for an adverse event was also similar between tenofovir and placebo with 3 percent of patients in each treatment arm discontinuing.

[Slide.]

The primary efficacy endpoint showed significant activity as the DAVG24 showed little change in the placebo group and a 0.61 log reduction in the tenofovir arm, and this was highly statistically significant.

[Slide.]

The mean change from baseline shows that the addition of tenofovir, one tablet, once daily, results in the rapid reduction from baseline in viral load to approximately 0.6 logs below baseline, and that is maintained out through week 24.

[Slide.]

Efficacy was also demonstrated in prospectively defined subgroup analyses. DAVG24 was analyzed according to patient's baseline HIV RNA of less than or greater than 5,000 copies/mL, CD4 counts of less than or greater than 200, male or female sex, or Caucasian or non-Caucasian ethnicity.

Tenofovir showed reductions of 0.4 to 0.7 logs and in each case, this difference was statistically different compared to placebo.

[Slide.]

Secondary efficacy endpoints further confirmed the activity. The percentage of patients with HIV RNA less than 400 copies/mL was 13 percent In the placebo arm compared to 45 percent in the tenofovir arm. For HIV RNA less than 50 copies/mL, 1 percent in the placebo arm and 22 percent in the tenofovir arm. DAVG24 for CD4 cell counts shows an 11 cell decrease in the placebo and a 13 cell increase in the tenofovir arm.

[Slide.]

The safety profile of tenofovir was similar to placebo. Grade 3 or higher adverse events were reported in 13 percent of patients in the placebo arm compared to 14 percent of patients in the tenofovir arm.

These are the adverse events which were reported in at least 1 percent of patients in either treatment arm, and importantly, each of these events occurs in less than 1 percent of patients in the tenofovir arm.

[Slide.]

Grade 3 or higher laboratory abnormalities were reported in 37 percent of patients in the placebo arm compared to 25 percent of patients in the tenofovir arm.

These are the laboratory abnormalities which occurred in greater than 1 percent of patients in either treatment arm and show a generally similar profile between tenofovir and placebo.

[Slide.]

Based on observations in animal studies, we were concerned about the potential for bone and kidney toxicity in tenofovir-treated patients. Because of that, we carefully monitored and conducted extensive analyses looking for these toxicities in our clinical studies.

For bone, we determined the bone fracture rate, and to assess the effects on the kidney we focused on changes in serum creatinine and phosphorus.

[Slide.]

I will present long-term data for these parameters from an integrated analysis of Studies 902 and 907.

In this analysis, there were 687 patients that received at least one dose of tenofovir 300 mg. 422 of these patients, as randomized, 191 patients following cross-over from placebo, and 74 patients following 48 weeks of either 75 or 150 mg in Study 902.

[Slide.]

480 of these patients had at least 48 weeks of tenofovir exposure and 156 patients had at least 72 weeks of tenofovir. The mean time on tenofovir was 58 weeks, and it ranged up to 143 weeks.

[Slide.]

The maximum toxicity grade for serum creatinine in Study 907 through 24 weeks shows a similar incidence of Grade 1 creatinine elevations between placebo and tenofovir, and there were no Grade 2 or higher creatinine abnormalities.

[Slide.]

Considering the longer term data, 5 percent of patients developed a Grade 1 creatinine abnormality while still no patient developed a Grade 2 or higher abnormality.

Our analysis indicates that these creatinine abnormalities are generally transient in nature.

[Slide.]

For the 32 patients with a Grade 1 creatinine elevation, 6 patients had the abnormality on a second consecutive visit. Of those 6 patients, only 1 patient had an additional 2 visits with the abnormality, and this patient discontinued the study secondary to pyelonephritis.

[Slide.]

Similar analyses were conducted for serum phosphorus. The maximum toxicity grade for hypophosphatemia in Study 907 in zero to 24 weeks shows 2 percent of patients in the placebo arm and 6 percent of patients in the tenofovir arm had Grade 2 hypophosphatemia. There were only isolated cases of Grade 3 or 4 abnormalities in either treatment arm. Six percent of patients in the tenofovir arm developed a Grade 2 abnormality through 24 weeks.

[Slide.]

Considering the longer term data with a mean of 58 weeks, that increased only slightly to 8 percent, while Grade 3 or 4 abnormalities remained uncommon. Our analysis indicates that the hypophosphatemia is also generally transient.

[Slide.]

For these 62 patients with Grade 2 or higher hypophosphatemia, 11 had two consecutive visits with the phosphate abnormality, and only one patient had three consecutive visits. Two patients interrupted tenofovir for the hypophosphatemia, but no patient discontinued the study for hypophosphatemia. Overall, there is no indication of clinically significant nephrotoxicity associated with tenofovir.

[Slide.]

Regarding bone, the bone fracture rate is similar between tenofovir and placebo. For the 210 patients that received placebo, there was a total exposure of 99 patient years during which 3 fractures were reported, yielding a fracture rate of 3.0 per 100 patient years.

Considering the 687 patients that received tenofovir 300 mg, there was a total of 778 patient years of exposure during which 13 fractures were reported, yielding a fracture rate of 1.7 per 100 patient years.

[Slide.]

Radiographs from 12 of these 13 patients were available and reviewed by Dr. Harry Genant, Professor of Radiology at UCSF. He concluded these fractures were the result of high-impact trauma and not due to bone fragility. Also, for the cases for which follow-up radiographs were available, normal bone healing was observed while tenofovir dosing was continued.

No vertebral compression fractures have been observed, and these are typically associated with osteoporosis. The tenofovir fracture rate is similar to placebo, and our analysis indicates that this rate has not increased with increasing tenofovir dosing duration.

[Slide.]

Overall, the safety profile of tenofovir 300 mg is similar to placebo through 24 weeks, and shows no significant change with extended dosing.

[Slide.]

Tenofovir 300 mg is a potent inhibitor of HIV replication and monotherapy resulted in a 1.2 log reduction from baseline. Tenofovir is active in highly treatment-experienced patients, and increased the percentage of patients that had HIV RNA less than either 400 or 50 copies/mL.

The activity is consistent across subgroups and appears durable through 48 weeks.

[Slide.]

As part of our efficacy evaluation, we also characterized the resistance profile of tenofovir in our clinical virology studies. In this protocol-defined study, DAVG24 was analyzed according to whether a patient's HIV expressed at baseline the M184V mutations associated with lamivudine resistance, any thymidine analogue mutation, or TAM, or any primary non-nucleoside or protease inhibitor resistance mutation.

While little change was observed in the placebo, reductions of 0.5 to 0.7 logs were observed for tenofovir. In each case, this was statistically significantly different when compared to placebo.

[Slide.]

Of particular interest was the activity against TAMs. Thymidine analogue mutations are now widely recognized to play a crucial role in nucleoside treatment failure. There are six thymidine analogue mutations, and these are selected in patients receiving either zidovudine or d4T. In those patients, the selection of TAMs results in a reduced clinical response. TAMs also confer cross-resistance to ddI in the presence of the M184V mutation abacavir.

[Slide.]

In this exploratory analysis, the DAVG24 was analyzed according to baseline TAM expression. For patients with no TAMS, tenofovir resulted in a 0.8 log reduction from baseline, for 1 or 2 TAMs, a 0.66 log reduction from baseline, and for 3 or more TAMs, a 0.4 log reduction from baseline.

Upon further analysis, 3 or more TAMs, which included either the M41L or L210W TAM, showed a diminished response to tenofovir, but still remained statistically significant. For 3 or more TAMs, which did not include either the M41L or the L210W, a decrease of 0.67 logs was observed, similar to the overall study.

[Slide.]

In addition to genotypic analyses, we also conducted a phenotypic analysis. This is another exploratory analysis in which DAVG24 was analyzed according to the baseline HIV susceptibility to tenofovir relative to wild-type virus.

For reduced susceptibility of up to 4-fold, decreases of 0.5 to 0.7 logs were observed for tenofovir, whereas, a decreased response for a susceptibility of greater than 4-fold was observed.

[Slide.]

We also performed post-baseline genotyping to identify the development of resistance mutations. Consistent with its activity, tenofovir suppressed the development of the mutations causing resistance to either protease inhibitors, non-nucleosides, or nucleosides.

While certain TAMs can cause a diminished response to tenofovir, tenofovir does not appear to select for TAM development. It does appear to select for the development of the K65R mutation as predicted from our in vitro studies, however, these arose in only 3 percent of patients.

[Slide.]

Overall, clinical virology substudies, we demonstrated that tenofovir is active against HIV, expressing common resistance mutations, including most TAMs. Also, there is a low incidence of tenofovir resistance mutation development.

[Slide.]

This is a highly favorable resistance profile and enhances tenofovir's other attributes, that it is safe and well tolerated, and it can provide durable antiviral activity.

[Slide.]

Based on the safety and efficacy data, tenofovir should be indicated in combination with other antiretroviral agents for the treatment of HIV infection in adults.

Dr. Bischofberger, in his concluding remarks, will provide further rationale for this indication.

[Slide.]

DR. BISCHOFBERGER: Dr. Jay Toole presented to you efficacy, safety, and clinical virology data from our controlled studies 901, 902, and 907, and based on these data, we propose that tenofovir is indicated for the treatment of HIV infection in adults.

In order to further evaluate this indication, we need to consider the study design and the patient population studied.

[Slide.]

Both our pivotal studies, Study 902 and Study 907, were placebo-controlled intensification studies carried out in highly treatment-experienced patients.

The reason why we chose this design is that, first of all, this is the patient population with an unmet medical need. Secondly, the resistance profile of tenofovir allowed for the addition of tenofovir alone as a single agent on the background therapy. Thirdly, such a placebo-controlled intensification design permits the clearest and most rigorous assessment of efficacy.

In these two studies, we were able to show that tenofovir has interviral activity in highly treatment-experienced patients, which, in general, is more difficult to achieve than in naive patients. However besides efficacy, tenofovir meets a number of other requirements which support its use in naive patients.

[Slide.]

One important consideration for the use of antiretrovirals in naive patients is adherence, its pill burden and the convenience of dosing. Tenofovir is administered as one tablet, once daily, and as such, meets that requirement.

Another important consideration is resistance development because not only can it lead to treatment failure, but it can also preclude future treatment options. Tenofovir has a lot potential for development of resistance mutations including TAMs.

Lastly, there is safety and tolerability. Tenofovir DF has a safety profile similar to placebo over 24 weeks, and there is no evidence of any tenofovir DF related typical ART dose-limiting toxicities.

So, given the efficacy of tenofovir in treatment-experienced patients along with meeting some of these other requirements, tenofovir should be a treatment choice in naive patients.

We currently have three other studies either ongoing or planned that will give us efficacy and long-term safety data on tenofovir DF.

[Slide.]

The first such study is Study 910. This is a rollover study for our patients who completed Studies 901, 902, or 907. A total of 575 patients were enrolled in this study, and these patients will be followed up from December 2002 for safety, virology, and a subset of these patients for bone mineral density.

This will then give us over four years of experience for patients treated with tenofovir DF 300 mg.

[Slide.]

The second study is our Study 903. This is also our first confirmatory study. Study 903 is a blinded, active-controlled study in antiretroviral and naive patients. The blinded portion of this study is of 96 weeks duration, and enrollment in this study was completed earlier this year, was 601 patients.

In this study, patients are randomized to one of two treatment arms consisting either of efavirenz, 3TC, d4T, or efavirenz, 3TC, tenofovir.

In this study, we are carrying out extensive bone evaluations in all 601 patients, consisting of bone mineral density analysis by DEXA scanning and following bone biomarkers for both the bone formation, which is osteocalcin, and bone-specific alkaline phosphatase, bone resorption, which is urinary N telepeptide in serum, C telepeptide.

In addition, we are also following vitamin D and parathyroid hormone.

This Study 903 constitutes our first confirmatory study. Our second confirmatory study is part of our pediatric development program.

[Slide.]

Our pediatric development program has recently been initiated following demonstration of safety of tenofovir DF in adults. A pediatric formulation is currently in development, and will be available in the first quarter of next year.

We have two, Phase I/II studies, which will be initiated very soon. One is Study 926. This is a 48-week study looking at pharmacokinetics, safety, and efficacy in 24 pediatric patients. The protocol for this study has been signed off and the study will be carried out at the National Cancer Institute.

In addition, we have Study 927, which is a single and multiple dose PK study in 30 pediatric patients. This is a study that is going to be carried out at various centers in France.

As a Phase III study, a second confirmatory Phase III study, we have proposed to the Agency a 48-week placebo-controlled study of tenofovir DF added onto an optimized background regimen in pediatric patients who have failed previous therapies. This will then also constitute our second confirmatory study.

So, with these three studies, Studies 910, 903, and the proposed Phase III pediatric studies, we have three studies in place that will give us efficacy in an expanded population, and it will also give us long-term safety data particularly with regards to the potential effects of tenofovir DF on bone.

In addition to these three studies, we have a number of other supportive studies planned including a study in renal and hepatic impairment and further drug interaction studies.

[Slide.]

So, with the data presented today, both preclinical and clinical, we demonstrated that tenofovir DF is an effective treatment of HIV infection.

Tenofovir DF is convenient, it is dosed once daily. It does not exhibit any clinically significant drug interactions. It has good tolerability with a safety profile similar to placebo over 24 weeks.

It has a favorable resistance profile both with regards to activity against resistant viruses and a low potential for development of resistance mutations including TAMs, and lastly, the treatment effect of tenofovir DF is durable through 48 weeks.

With that, I would like to thank you for your kind attention.

DR. GULICK: Thanks, Dr. Bischofberger and Dr. Toole for your presentations.

As we stated earlier, we would like to hold questions for the sponsor at this point and go ahead and proceed with the FDA presentation. Dr. Kim Struble is going to start.

DR. STRUBLE: Thank you.

[Slide.]

My presentation will include an overview of the NDA submission followed by a summary of the efficacy and clinical virology results. Then, Dr. Jim Farrelly will give a summary of the nonclinical assessment of bone abnormalities. I will then conclude with a clinical assessment of the bone abnormalities, followed by a brief summary of the second study for traditional approval, and a summary of our regulatory issues.

[Slide.]

Gilead Sciences submitted a New Drug Application on May 1st of this year for the tenofovir DF 300 mg, given once daily, for the treatment of HIV infection.

[Slide.]

In this NDA submission, four clinical studies evaluating tenofovir tablets were submitted, including two supportive and two principal studies.

The first supportive study, Study 901, was a 35-day, Phase II dose finding trial in treatment-naive and treatment-experienced patients.

Study 908 was a compassionate use safety study in patients with limited therapeutic options.

There are two principal studies, Studies 902 and 907. Both of these studies were randomized, double-blind, placebo-controlled for 24 weeks.

[Slide.]

The two principal studies, Studies 902 and 907, were both similar in design, the safety and efficacy of tenofovir compared to placebo when added to a stable antiretroviral regimen was assessed in treatment-experienced patients.

Both studies enrolled patients with similar baseline characteristics. Both studies were predominantly Caucasian men, approximately 41 years of age, and received about four or five years of prior antiretroviral therapy.

However, differences were noted in the two studies, and that was on the baseline HIV RNA. In Study 902, the baseline RNA was between 400 and 100,000 copies, whereas, in Study 907, the baseline RNA was restricted to between 400 and 10,000 copies.

Consequently, the mean baseline RNA was slightly higher in 902, and the mean baseline CD4 cell count was slightly higher in 907.

[Slide.]

The primary efficacy endpoint for these studies was the time-weighted change in log HIV RNA over 24 weeks or DAVG. We think that this analysis is useful for assessing any viral activity in which plasma levels below assay limit may not be frequently achieved.

Therefore, we concluded that DAVG is an acceptable endpoint for evaluating virologic responses in treatment-experienced patients, such as those enrolled in the two pivotal studies, Study 902 and 907.

Secondary endpoints include the proportion less than 400 and 50 copies.

[Slide.]

I will now show the HIV RNA results for the placebo and the tenofovir 300 mg dose group.

[Slide.]

This slide here shows the mean change from baseline in HIV RNA over 24 weeks for Studies 902 and 907. As you can see, consistent results were seen in both studies. In both studies, statistically significant differences of approximately 0.5 to 0.6 log were seen for the primary endpoint favoring tenofovir over placebo.

In Study 902, the mean DAVG for the placebo group was an increase of 0.2 logs compared to a decrease of 0.58 logs for the tenofovir group.

In Study 907, the mean DAVG at week 24 for the placebo group was an increase of minus 0.02 log for the placebo group and a decrease of minus 0.61 log for the tenofovir group.

[Slide.]

This slide shows the proportion of patients less than 400 and less than 50. The less than 400 data is in yellow, and the less than 50 data is in orange.

In Study 902, numeric differences favoring tenofovir over placebo were seen at week 24. At week 24, the proportion of patients less than 400 was 19 percent in the tenofovir arm compared to 7 percent in the placebo arm.

The proportion of patients less than 50 was 11 percent in the tenofovir arm compared to zero percent in the placebo arm.

In Study 907, statistically significant differences favoring tenofovir over placebo was seen for both analyses. At week 24, the proportion less than 400 was 40 percent for the tenofovir group compared to 11 percent for the placebo group.

For the less than 50 analysis, it was 20 percent for the tenofovir group compared to only 1 percent for the placebo group.

[Slide.]

I will now discuss the CD4 count results for the placebo and tenofovir 300 mg dose groups.

[Slide.]

This slide shows here the mean change from CD4 over 24 weeks in Study 902. This graph is a bit unusual in that the placebo group has a sharp increase at the last time point. This may, in fact, be due that there is only 22 patients available at week 24 and the data was quite variable.

The mean DAVG for this study was a decline of 11 cells for tenofovir group, and a decline of 4 cells for the placebo group. There were no differences between the two groups at any time point.

[Slide.]

This is the mean change for CD response for Study 907. The mean DAVG for the tenofovir group was an increase of 13 cells compared to a decrease of about 11 cells for the tenofovir group resulting in a net treatment difference of about 23 cells. Statistically significant results favoring tenofovir over placebo was seen at every time point.

[Slide.]

To further investigate the modest responses seen in these two studies, we looked at the CD4 cell count response by baseline CD4 from the pooled analysis of 902 and 907. We chose 200 cells because that was the protocol randomization scheme.

As you can see here, CD4 responses were similar for patients with less than 200 cells and greater than 200 cells. We felt that this finding was important for patients with lower baseline CD4 count cells for minimizing the risk of opportunistic infections over time.

[Slide.]

In summary, the mean viral load reductions we saw were similar for both studies, and statistically significant differences of about 0.5 to 0.6 log favoring tenofovir over placebo were seen.

For the less than 400 and the less than 50 analysis, numerical differences favoring tenofovir over placebo was seen in 902, and statistically significant differences favoring tenofovir over placebo was seen in 907, however, there are modest increases in CD4 cell counts in Study 907, and no differences for CD4 counts between tenofovir and placebo were seen in Study 902 over 24 weeks.

[Slide.]

It is important to note that the study populations in Studies 902 and 907 may not have been optimal for observing large increases in CD4 cell counts, given the fact that only one new drug was added to a stable regimen.

The addition of one new agent did not produce a substantial increase in CD4 cell counts over time.

It is clear that further evaluations of CD4 responses in studies with different designs are needed.

[Slide.]

I will now go over the clinical virology results.

[Slide.]

Prospective analyses were conducted by Gilead based on the HIV RNA response by prospectively defined baseline mutation subgroups in both Studies 902 and 907.

To further explore these issues, we conducted several exploratory analyses to further investigate RNA response according to the presence or absence of specific NRTI mutations. These analyses were done to determine if the specific mutations or mutational patterns affected response to tenofovir.

[Slide.]

However, it is important to note the limitations of these exploratory analyses in that the large number of potential comparisons does limit the ability to test for statistical significance.

Also, there was a limited number of patients for some primary NRTI and multi-drug resistant mutations to determine clinical significance.

Given these limitations, we are soliciting your feedback today on the types of exploratory analyses conducted and recommendations for labeling.

[Slide.]

First, I will start out with the genotypic results.

[Slide.]

HIV RNA response by the presence or absence of thymidine analogue mutations was assessed. The six common thymidine analogue mutations, or TAMs, are defined as amino acid changes in positions 41, 67, 70, 210, 215, and 219.

[Slide.]

This slide here shows the mean HIV RNA response by baseline TAMs, specifically, the 67, 70, and 219. We see here that these mutations did not appear to affect tenofovir efficacy. In fact responses were similar regardless if these baseline mutations were present or absent.

[Slide.]

This slide here shows the HIV RNA response by the presence or absence of the 215, 210, and 41 mutation. It appears here that these mutations affect tenofovir efficacy and that responses were approximately 0.5 log less if these mutations were present at baseline.

We then conducted subsequent analyses to determine the impact of these mutations.

[Slide.]

In the previous slide, we showed that the 215 mutation appeared to affect tenofovir efficacy, but, in fact, it was felt that this mutation may not have directly impacted the overall results.

[Slide.]

Patients with the 215 mutation, along with the 41 or 210, had a mean DAVG of minus 0.25 logs. Compared to patients with the 215 without a 41 or 210, had a mean DAVG of minus 0.7 logs. Therefore, we concluded that it is the presence of the 41 or 210 mutation that affected response, and not necessarily the 215 mutation.

So overall, we concluded that it is the presence of the 41 and 210 mutation that affects overall tenofovir efficacy. Patients that do not have a 41 or 210 at baseline had a mean DAVG of minus 0.79 logs compared to patients with the 41 or 210 mutation, they had a mean DAVG of minus 0.26 logs at 24 weeks.

[Slide.]

It also appeared that the number and types of TAMs affected tenofovir efficacy. Patients that had no TAMs at baseline had the largest declines in HIV RNA, and this subgroup had a mean DAVG of minus 0.8 logs.

Patients with one or two TAMs, or three or more TAMs, that did not include a 41 or 210, had approximately a mean DAVG of minus 0.65 log at week 24. Tenofovir actually appeared somewhat diminished in patients with three or more TAMs that included the 41 or 210. The mean DAVG for this subgroup was minus 0.21 logs.

[Slide.]

The 74 mutation also appeared to affect tenofovir efficacy. Eighteen patients expressed this mutation at baseline, and did not appear to respond to treatment. We also then evaluated this mutation to see if the presence or absence of other NRTI mutations actually affected response.

We found that the response rates were similar regardless if the 41 or 210 mutation was present along with the 74.

The 65 mutation was shown to reduce susceptibility to tenofovir in vitro. Six patients expressed this mutation at baseline, and did not appear to respond to tenofovir treatment over 24 weeks. However, more data is needed when patients express this mutation to make any definitive conclusions at this time.

[Slide.]

Now, I will review the phenotypic results.

[Slide.]

Phenotypic analyses were done to determine if tenofovir baseline susceptibility affected response. Patients with tenofovir susceptibility within 4-fold or wild-type had a mean DAVG of minus 0.61 compared to patients with tenofovir greater than 4-fold or wild-type had a mean DAVG of minus 0.12, indicating that patients with reduced susceptibility to tenofovir at baseline had diminished activity.

[Slide.]

So, in summary, we concluded that the genotypic data suggest potential for some cross-resistance between tenofovir and specific NRTI mutations or patterns of mutations.

However, too few patients expressing some primary NRTI or multi-drug resistant mutations were available to determine clinical significance.

We agree with Gilead's analysis earlier presented in that no cross-resistance between tenofovir and lamivudine was seen.

[Slide.]

We also concluded that it was the presence of the 41 or 210 mutation that diminished tenofovir efficacy, whereas, mutations at positions 67, 70, 215, and 219 did not affect tenofovir efficacy.

The number and types of TAMs did affect tenofovir efficacy, and that these responses were reduced in patients with three or more TAMs, which included the 41 or 210.

The 65 and 74 mutation may also affect efficacy, and reduced susceptibility to tenofovir at baseline also diminishes tenofovir efficacy.

[Slide.]

Now, I will briefly describe the safety results. Treatment with tenofovir appeared to be well tolerated and similar to placebo. The most common adverse events associated with tenofovir use included asthenia, headache, diarrhea, nausea, and pharyngitis.

GI events, such as diarrhea, flatulence, nausea, and vomiting occurred greater in the tenofovir group compared to placebo.

In addition to these events, we also evaluated the nonclinical and clinical effects on bone abnormalities.

Now, Dr. Jim Farrelly will present the nonclinical assessment of bone abnormalities.

DR. FARRELLY: Good morning. My name is Jim Farrelly. I am the Pharmacology Supervisor in the Division of Antiviral Drug Products.

Today, I will present a compilation of bone toxicities discovered in the nonclinical toxicology safety studies carried out to support the use of tenofovir disoproxil fumarate or tenofovir DF in the clinic. Tenofovir DF is an esterified prodrug of tenofovir, which is a nucleotide analogue reverse transcriptase inhibitor and is rapidly converted to tenofovir in vivo.

As is the case for most new chemical entities submitted to an IND, the initial animal studies carried out to allow administration of tenofovir DF to human in a Phase I study were of a shorter duration than those carried out to support administration in a Phase II or a Phase II study.

Safety studies in a rodent and a non-rodent species are, as a general rule, expected by the Agency to support clinical dosing. In the submission of the original IND under which tenofovir DF was to be studied, a four-week safety study in rats and a four-week safety study in dogs was submitted for review.

[Slide.]

Daily dosing for four weeks resulted in essentially no toxicity in rats dosed up to 500 mg/kg/day.

In dogs, doses up to 30 mg/kg/day showed minor toxicity in kidney, but no toxicity to bone. Thus, at the outset of a one-month clinical trial with tenofovir DF, bone toxicity in nonclinical studies was not seen yet, and therefore, was not a perceived concern.

[Slide.]

However, with longer term dosing, bone toxicity started to appear in the animal studies. In the rat, dosed up to a 1,000 mg/kg/day for 13 weeks, bone toxicity was seen, as well as adverse effects on the renal tubules. By 42 weeks, frank bone toxicity appeared at the two highest doses.

This toxicity presented as decreases in bone mineral content and density, cortical thickness of the femur, increases in deoxypyridinoline, a marker of bone resorption were found, as well as increase in osteocalcin, a marker of bone formation.

Plasma phosphorus increases, as well as increases in urinary calcium and phosphorus were found. Parathyroid hormone increases were also seen.

[Slide.]

Dogs, dosed daily up to 30 mg/kg/day for 13 weeks exhibited toxic effects in the kidney that was seen as tubular chiromegaly and chronic interstitial nephritis.

At 13 and 42 weeks, dogs dosed at 30 mg/kg/day exhibits bone toxicity presented as decreases in bone mineral content and density.

Changes in biochemical markers of bone metabolism, increased urinary N telepeptide, increased urinary calcium and phosphorus, increased bone specific alkaline phosphatase, and decreased 1,25-dihydroxy vitamin D3 were consistent with bone activation.

After a 13-week period in the absence of drug, there was some evidence of recovery.

[Slide.]

A 13-week gavage toxicology study in mice, carried out as a dose range-finding study for a two-year carcinogenicity evaluation was carried out.

No specific bone effects were seen in this study. Toxicity in the kidney and duodenum defined the maximum tolerated dose for the carcinogenicity study.

The carcinogenicity study has not been completed, but it will be interesting to examine it for the possible appearance of bone toxicities arising as the result of long-term chronic dosing, which would be in the fourth species.

[Slide.]

As the studies in rats and dogs were being carried out, the effects of tenofovir DF were being examined in monkeys. An early study dosed cynomolgus monkeys with tenofovir, not tenofovir DF, intravenously for 14 days at doses up to 25 mg/kg/day, which is approximately equivalent to a dose of tenofovir DF of 50 mg/kg/day based on molecular weight differences. No bone toxicities were seen in this study. There were, however, treatment-related effect in the kidneys of the monkeys.

[Slide.]

Shortly after the start of clinical trials of tenofovir DF, efficacy studies on the effect of tenofovir, again not tenofovir DF, in monkeys infected with SIV were carried out and reported to the Agency.

Rhesus monkeys, some infected and some not infected with SIV, were dosed subcutaneously with tenofovir. Bone toxicities were seen in monkeys after greater than 10 months of daily dosing of 30 mg/kg/day.

[Slide.]

The toxicity was characterized as abnormal growth plates and trabecula of the femur and ribs. Also seen were bone deformities and displacements, rib fractures, reduced bone density and bone loss in the spine or pelvis.

The animals showed a moderate to marked reduction of serum phosphorus with elevate alkaline phosphatase levels. Non-hyperglycemic glucosuria and proteinuria were also seen. Serum calcium was unchanged, but unfortunately, urinary phosphorus and calcium were not measured.

Pregnant dams, dosed from the second trimester, gave birth to two offspring, but showed bone toxicity at 2 and 7 1/2 months of age. These animals, however, were dosed throughout the study at 30 mg/kg/day with tenofovir.

Other individual newborns, dosed for two years with 10 mg/kg/day, showed no bone toxicity. The fact that bone toxicities were seen in the studies using monkeys prompted the Division to ask that special monitoring for bone toxicities in the 42-week studies in rats and dogs, as well as in the clinic, be carried out.

[Slide.]

These studies concluded that chronic treatment of rhesus monkeys at 30 mg/kg/day can result in a mineralization defect in developing and growing cortical bone consistent with a condition referred to as osteomalacia. The reversibility in the defect in mineralization was seen when the dose was reduced to 10 mg/kg/day or treatment was stopped.

[Slide.]

Finally, it should be stated that no bone defects were seen in a battery of four reproductive toxicology studies in rats and rabbits. In the studies, doses as high as 600 mg/kg/day in the rat and 300 mg/kg/day in the rabbit were administered.

The studies examined the effect of tenofovir DF on mating and fertility parameters in the rat, teratogenicity in the rat and rabbit, and peri- and post-natal development in the rat again.

[Slide.]

It is clear that tenofovir and tenofovir DF induce bone toxicities in three animal species. Toxicity is consistent with a diagnosis of osteomalacia, however, the mechanism whereby the toxicities arise is not known.

[Slide.]

The sponsor hypothesizes that the bone effects are secondary to a negative phosphate balance associated with drug-related impairment of intestinal phosphate absorption and/or renal reabsorption of phosphate, and not a direct toxic effect on bone.

The evidence based on animal toxicity studies, as well as in vivo and in vitro mechanistic studies presented by the sponsor up to this point, is consistent with the hypothesis, but at the present time, the mechanism must be considered to be unknown.

At this time, Dr. Struble will now continue with the Division's assessment of the submission.

[Slide.]

DR. STRUBLE: After reviewing the exposure data and bone abnormalities noted in the animal studies, it does give us some reassurance that there is a margin of safety for the proposed 300 mg dose in humans.

Bone mineral density reductions in rats and dogs were seen at 6 to 10 times higher than that of human exposures, and osteomalacia in monkeys was seen at 12 times higher than that of human exposures.

[Slide.]

We found no clinically significant changes in phosphate, calcium, PTH or bone mineral density observed over time in Studies 902 and 907, however, it is important to note that PTH and bone mineral density data was only available for a small subset of patients.

[Slide.]

In Study 902, the incidence of fractures was 5.5 percent. The proportion of patients with fractures in this study is higher than that seen in FDA meta-analysis of 13 trials in which patients who developed fractures was about 2 percent.

The observations seen in Study 902 may, in fact, be due to the small sample size, but further investigation of this potential safety signal was warranted.

[Slide.]

This slide here shows the fracture rate in 6-month intervals. The fracture and patients is in white, and the rate and person years in 95 percent confidence intervals is in yellow.

We concluded that the fracture rate does not appear to increase over 6-month time intervals.

[Slide.]

So, after review of the entire nonclinical and clinical safety and pharmacokinetic data, we concluded that it is probably unlikely that tenofovir-related fractures would occur over 48 weeks.

This is assuming that the mechanism is mediated by renal phosphate wasting or decreases in intestinal absorption of phosphate.

We noted that no significant changes in renal parameters, in particular phosphate, were seen, and that incidence and severity of phosphate abnormalities did not worsen with increasing durations of tenofovir.

The rates of fractures did not appear to increase over 6-month time intervals. Review of the individual fracture data in Studies 902 and 907, we concluded that these fractures were probably a result of high trauma and accidental injury, and there did not appear to be an imbalance in fragility fractures.

[Slide.]

However, it is important to note that there are still insufficient numbers of patients receiving prolonged tenofovir treatment and a lack of a control arm past 24 weeks. It makes it difficult for us to conclude whether or not tenofovir would cause clinical fractures over time or if the risk would increase over time.

[Slide.]

Now, I will discuss the traditional approval plans.

[Slide.]

In general, we have required two studies assessing HIV RNA for a minimum of 48 weeks. Gilead has summarized their first study, Study 903, which compares tenofovir to d4T on a background of 3TC and efavirenz treatment in treatment-experienced patients for 96 weeks.

The second study they are proposing is a study in treatment-experienced children.

[Slide.]

This study is a two-part hybrid, and this study design was in part discussed at the January 2001 advisory committee on study designs and treatment-experienced patients. One hundred children will be enrolled in this study.

Children will have HIV RNA greater than 30,000 copies, CD4 percent less than 20 percent or less than 30 percent with an OI in the past 90 days. All children would have been experienced with at least one member of each drug class, and must be on a stable background regimen for at least 8 weeks prior to study entry.

At study entry, patients will be randomized to receive tenofovir or placebo over two weeks. At week 2, their stable background regimen will be changed to an optimized background regimen based on resistance testing conducted at baseline.

Patients would then continue on tenofovir or placebo for the remaining 46 weeks. The proposed endpoints for the study is the DAVG at week 2 and at week 48. The first part of the study assesses the contribution of tenofovir over placebo to a background regimen.

The second part of the study would assess the durability of tenofovir compared to placebo when given with an optimized background regimen.

[Slide.]

Now I will discuss the summary of the regulatory issues, which we will discuss this afternoon.

[Slide.]

Gilead is seeking an indication for the treatment of HIV infection based on the results of Studies 902 and 907, however, the study populations in these studies were quite select given that they were both antiretroviral-experienced with a relatively low baseline viral load and high CD4 cell counts at entry.

[Slide.]

We are interested in the discussion this afternoon regarding the most appropriate indication for tenofovir - specifically, should it be given for the treatment of HIV infection, and that this indication would encompass the entire spectrum of HIV and disease including naive and treatment-experienced patients, or should tenofovir be recommended for the treatment of HIV infection in patients who have received prior antiretroviral therapy.

[Slide.]

The second issue relates to the bone abnormalities. The nonclinical data we saw reductions in bone mineral density in three different species, and the exact mechanism or mechanisms unknown, but it is probably due to renal phosphate wasting or decrease in intestinal absorption of phosphate.

[Slide.]

The clinical data, we saw no significant changes in phosphate, calcium, PTH, or bone mineral density over time, but again, PTH and bone mineral density was only available for a small subset of patients.

The rates of fracture did not appear to increase over 6-month intervals. It is clear that controlled safety data in more patients for longer durations are needed.

[Slide.]

We are interested in your assessment today of the nonclinical and clinical data with regard to bone effects. Gilead has also studied the bone abnormalities in several nonclinical studies. Also, Study 903 will provide comparative data for bone mineral density and bone biomarkers for approximately 600 patients over 96 weeks.

We would like to hear your recommendations today, if there are additional nonclinical or clinical studies that should be conducted to further evaluate tenofovir-associated bone abnormalities.

[Slide.]

With regard to clinical virology data, this NDA did contain more data than submitted for any other antiretroviral drug product. Both prospective and exploratory analyses were conducted, however, there were some limitations of the exploratory analyses conducted and presented today.

There are a limited number of patients for some primary NRTI and multi-drug resistant mutations to determine the true clinical significance.

Also, the large number of potential comparisons does limit the ability to conduct tests for statistical significance.

[Slide.]

We would like your comments today on the clinical resistance analyses conducted during the development of tenofovir, and would like to hear recommendations for the types of clinical virology analysis that should be conducted for future antiretroviral drug development programs and suggestions for the type of resistance data and analysis that warrant display in package inserts.

[Slide.]

Regarding traditional approval and accelerated approval and Phase IV commitments, we would like your comments on the proposed second study for traditional approval in treatment-experienced patients.

Finally, we would like comments on other study designs or patient populations that should be studied as Phase IV commitments.

[Slide.]

Lastly, I would like to acknowledge and thank the entire tenofovir review team.

Thank you.

DR. GULICK: Thank you, Dr. Struble and Dr. Farrelly. Let's take a break now. Let's reconvene at five minutes of 11:00 and then we will proceed with the question period.

[Break.]

DR. GULICK: Welcome back, everyone. A couple of announcements. We changed our plans again and will have the meeting in this room all day. We are not going to change rooms after lunch as we said before. We have given galoshes to Dr. Wong and DeGruttola.

One of the committee members joined us late. Dr. Wood, could you speak your name and where you are from.

DR. WOOD: I'm Dr. Lauren Wood and I am from the National Cancer Institute in Bethesda, Maryland.

DR. GULICK: Thanks. Dr. Lukert is out there in cyberspace. I am not sure we can hear her or if she can hear us.

DR. GULICK: This is a period now for questions from the committee members and our guests. People can address questions either to the sponsor or to the agency. Dr. Pomerantz is taking the lead there, so we will let him start.

DR. POMERANTZ: It is my last committee meeting so I thought I would ask a couple of questions. Questions for the sponsor, I have a couple. First, you did say that there was a death in 902 and that it was not considered due to the drug, according to the investigator. Can you tell us what happened to that patient?

DR. TOOLE: That was a patient with a significant history of depression and, during the study, committed suicide with the ingestion of several toxic agents.

DR. POMERANTZ: Thank you. The second question is in 901, the monotherapy study. Was there any resistance data done prospectively or retrospectively on the primary or lack of resistance in those viruses?

DR. TOOLE: We did not see the development of any resistance mutations over the course of 28 days. Interestingly enough, we did do baseline genotyping. If you recall, we saw a somewhat lesser response in the 600 milligram dose group compared to the 300 milligram dose group and, retrospectively, we have identified it resulted from the presence of the M41L and study of other TAMs in two patients in the 600 milligram dose group.

DR. POMERANTZ: You don't know whether those viruses were primary-resistant in those patients or they developed it over time, I assume, primary resistance being transmission of a primary-resistant virus strain.

DR. TOOLE: We don't know that.

DR. POMERANTZ: The final thing, and I am sure this is going to let our endocrinological associates start off, but you had talked a little bit about the effects on the kidney and we saw some creatinine and such data. Were there any 24-hour urines or spot-urine lights done during those studies looking at phosphate, calcium, osmolality, the usual?

DR. TOOLE: We did studies looking at both calcium fractional secretion and phosphorous fractional secretion. In neither of those did we see significant changes when compared to placebo from baseline through week 24.

DR. POMERANTZ: Those were done in spots, or 24-hour urine--

DR. TOOLE: Those are spot collections.

DR. POMERANTZ: You have data for that?

DR. TOOLE: Yes.

Slide 257, please.

[Slide.]

The median change from baseline of phosphorous fractional secretion. These patients came in with phosphate fractional secretion of about 10 percent and, over the course of 24 weeks, there was no significant difference between placebo and tenofovir.

256, please.

[Slide.]

In addition, now, with the extended data out beyond two years, there remained little change in the phosphorous fractional secretion.

DR. BONE: Excuse me. Can you show the previous slide?

DR. TOOLE: Slide 257, please.

[Slide.]

DR. BONE: That's it. Could I just chime in for a second on this. It does appear, however, that the fractional excretion of phosphorous is higher at every single time point in the treatment group than in the other group.

DR. TOOLE: Correct. But it was not significantly different between them.

DR. BONE: That would depend, actually. It wasn't significant at any one time point, but I suspect that, if a sign-ranked study had been used to look at the whole thing, the fact that there was a change in every case in the same direction would have led to a different conclusion.

DR. TOOLE: Correct.

DR. GULICK: Two reminders as we proceed with the questions. One is, let's try to stick to questions on information right now, actually as Dr. Pomerantz showed us. So we will stick to the debating--we will leave those issues really until the afternoon. So stick to points of clarification or information.

DR. POMERANTZ: Just to finish that. You have no twenty-four hours urines on any of these patients, not only looking at calcium phosphate but osmolality, sodium, potassium.

DR. TOOLE: No; those are all spot analyses.

DR. GULICK: Dr. Kumar.

DR. KUMAR: I have a question regarding your safety data. Both you and the FDA showed that osteomalacia was seen in animals. But when you showed all the clinical data, both in 902 and 907, patients that were entered, the average age was 41 and there were only 15 persons--is there anything that you can tell us that shows that this safety data that you showed, there is no increase in fracture rate that we could take and say that older women, any data in the expanded access that you could show us that they did not have a higher fracture rate?

DR. TOOLE: The expanded access program has now enrolled 5000 patients in the U.S. and worldwide, 3000 patients in the U.S. That study began only in March of this year, and we have limited safety data on that study to date. We do have a compassionate access study, Study 908, which tenofovir was provided to patients with advanced HIV infection with CD4 counts less than 50.

At the time of filing, the mean duration on treatment was 44 weeks. In that study, the fraction rate was also similar to placebo. Again, there was no evidence of any clinically significant renal toxicity associated with tenofovir.

DR. KUMAR: But my question specifically was, in both 902 and 907, mainly it was mean and the age group was 41. My question is the older women are more susceptible to fracture, whether you had anything that you could see when you expanded that.

DR. TOOLE: No data are available yet on that. However, an important point to make is that postmenopausal women are more susceptible to fracture on the basis of osteoporosis. What we observed in our animal studies was osteomalacia.

DR. GULICK: Dr. Schapiro?

DR. SCHAPIRO: Could I look at the slide that you showed, Study 901, changes in viral load.

DR. TOOLE: 615, please.

[Slide.]

DR. SCHAPIRO: The week 35 comparison between the 300 and 600; the week 35 comparison between the 300 and 600 milligram dose, there were eight patients in each arm. Those included naive and experienced.

DR. TOOLE: Correct.

DR. SCHAPIRO: How many were actually experienced in that comparison?

DR. TOOLE: In the 300 milligram dose group, there were four treatment-naive and four treatment-experienced patients. The treatment-naive patients had a mean log change of 1.4 logs.

DR. SCHAPIRO: How many were experienced in the 600 milligram group?

DR. TOOLE: I don't recall.

DR. SCHAPIRO: So, actually, with the 300 and 600, we were comparing three to four treatment-experienced patients in each arm?

DR. TOOLE: Correct.

DR. SCHAPIRO: Could we see the CD4 results for those two groups?

DR. TOOLE: I didn't show the CD4 results for Study 901.

DR. SCHAPIRO: Do you have them? I would like to see them for those two doses.

DR. TOOLE: Slide No. 1, please.

[Slide.]

These are the mean changes in CD4 cell counts from baseline to Day 35. There was a lot of variability in this measurement. Of course, at 35 days, the placebo group is showing a 74 percent increase.

DR. SCHAPIRO: What would the explanation be for such a better response for 600 than for 300?

DR. TOOLE: I think the variability we are observing--this is probably based on the fact that there are very few patients enrolled. There were only eight patients per treatment group. The variability measurements reflected in these numbers. I don't think there is anything significant in the difference between the 300 and 600 milligram group.

DR. SCHAPIRO: But that is just based on the four to three experienced patients?

DR. TOOLE: No; these are the data for all patients, all eight patients.

DR. SCHAPIRO: Were there any other data on 600 after this very small comparison?

DR. TOOLE: No.

DR. GULICK: Would you remind us of the median CD4 cell count on this study?

DR. TOOLE: Again, we don't have the medians. We did not pursue the 600 milligram dose after Study 901. That was based on--we also did an earlier study looking at intravenous and infused tenofovir. We administered doses at that 1 milligram per kilogram and 3 milligrams per kilogram. The 3 milligrams per kilogram dose corresponds to about five times the dose that received the 300 milligram oral dose and there were no significant log changes there after two weeks of dosing. They were in the 1.2, 1.4 log range. So they achieved maximum activity with the 300 milligram dose.

DR. SCHAPIRO: I bring this up because the drug-experienced patient in other drugs that we approve, we later found that different doses are appropriate ones. So it would be important to look into the drug-experienced patients to see--you showed the interaction--I think you mentioned that a retonovir and lopinivir Kaletra was done, had an interaction?

DR. TOOLE: 126, please.

[Slide.]

So tenofovir caused a slight decrease in the Cmax, Cmin and AUC for lopinavir. So there was an approximately 15 percent decrease of lopinavir in both Cmax and AUC and a decrease of approximately 11 percent for Cmin. In discussions with the pharmacokineticist at Abbott and also with outside experts, this was deemed to be not clinically significant because the trough concentration still remains significantly above that required to inhibit the HIV replication in terms of both the IC50 and the IC90. I think the IC90 still remained more than 40-fold above that required.

DR. SCHAPIRO: Was that the drug-experienced patients or the drug-naive patients?

DR. TOOLE: This was done in naive type of patients.

DR. SCHAPIRO: So the levels you are measuring are the wild-type virus. Do you have an effect of Kaletra on tenofovir?

DR. TOOLE: There is an approximately 30 percent increase in this cohort of tenofovir AUC. We think that could be--that cohort was supposed to have taken tenofovir with food. And yet the AUC that we observed in this cohort was bit more consistent with tenofovir administered in the passive state. So now we are going to go back and reexamine that in more controlled study to see if there was interaction.

DR. SCHAPIRO: Since many patients received an higher active dose of retonovir, 400 milligrams, was there an interaction study--possibly if it is retonovir, we would see even a greater increase with three times the amount of retonovir.

Have any interactions been done with the 400 dose of retonovir? Has it been given to any of these patients?

DR. TOOLE: It has not been given.

DR. GULICK: Dr. Bone and then Dr. Stanley.

DR. BONE: Thank you. I have several questions in no particular order. In the clinical studies, you graded patients whose serum phosphorous fell to below 3.2 milligrams per deciliter as Grade 1. In most laboratories, the lower limit of the reference range is about 2.5. I would be very interested in seeing the data for all patients who fell below 2.5 and all patients who fell by, say, 0.5 from their baseline as you did with one of the other measurements.

You probably don't have that at the moment, but I would like you to get that out. I am sure your statisticians can pull that out by this afternoon, unless you have it right now.

DR. TOOLE: No, but I will say that we used a central laboratory for all the clinical studies. The 2.2 was the lower limit of the normal for phosphorous in that central--

DR. BONE: Really. That is more than most laboratories' lower limit. So maybe you would look at the ones who fell by 0.5 or something like that because that is quite a low lower limit.

I think it would be interesting to see what the rate of decline of patients who had a declining serum phosphorous would be even if they were not frankly hypophosphatemic.

The second question has to do with the monkey study that was done at four times the predicted human dose. Do you have histology from that study?

DR. TOOLE: No; we don't.

DR. BONE: You don't. So the only histology we have in monkeys demonstrates the osteomalacia at the higher dose. I guess that what you are telling me is that we don't have a no-effect dose for that histologic abnormality.

DR. TOOLE: The animals that were dosed at 10 milligrams per kilogram, and these are monkeys that began dosing at 2 mls, those monkeys had clear clinical observations in adult fractures. Bone biopsies were taken for those animals that had received the 10 milligrams per kilogram dose.

On dose reduction, on a 30 milligram per kilogram dose, animals that were begun as neonates at the 10 milligram per kilogram dose, and that is corresponding to about a fourfold increased level compared to the human dose, those animals are out more than two years now and there are no clinical findings which would indicate that these--at biopsy.

DR. BONE: But there has been no histologic examination.

DR. TOOLE: No histologic examination.

DR. BONE: So we don't have histology. We don't have a no-effect dose demonstrated by histology; is that right?

DR. TOOLE: By histology; that is correct.

DR. BONE: In one of the FDA presentations, Dr. Farrelly's presentation, he mentioned that, in the dog study, the 42-week dog study, the 125 dihydroxy-vitamin-D levels were found to be reduced. Do you have similar information for any of your other studies?

DR. TOOLE: Vitamin D has not been assessed. Vitamin D is being assessed in the confirmatory study, Study 903.

DR. BONE: Surely you have samples.

DR. TOOLE: We were going to define a change in vitamin D levels in the course of Study 902, but we had an inadequate baseline sample in which to clear the further analysis.

DR. BONE: I think I will follow Dr. Gulick's recommendation and we will discuss that a little further later. Let's see. That is all for now. I will let somebody else take a turn. I will ask some more questions later.

DR. GULICK: Dr. Stanley and then Dr. Hamilton.

DR. STANLEY: Just a couple of things to clarify. On the graph that you showed the decreased phosphate and increased creatinine kinase on only one visit, was that during the study continuing drug or was that after discontinuation of the drug?

DR. TOOLE: I'm sorry; which graph was that?

DR. STANLEY: No. 46 and I think 43, you said you had visits with grade 1 creatinine and--

DR. TOOLE: Those were all continuing on study. We monitored laboratory abnormalities while still on drug.

DR. STANLEY: So those were on drug.

DR. TOOLE: Yes.

DR. STANLEY: And then a question about the resistance data. You showed that, at 24 weeks, there was 3 percent occurrence of the K65R mutation. Have you looked at anything further out beyond 24 weeks and also, even at that time point, did you see any change in--any clinical susceptibility changes or in vitro changes?

DR. TOOLE: The response after the development of the K65R was typically variable. In Study 907, there were five patients who developed the K65R. In three of those patients, they had little reduction in viral load from baseline. One patient developed the K65R but maintained a 0.7 log reduction. A fifth patient developed a K65R and showed a clear trend toward baseline. However, that patient also developed a primary non-nucleoside resistance mutation. That patient was also receiving nevirapine.

With regard to extended data, we have recent data which we have not yet shared with the FDA which will presented at ICAAC. In Study 902, there were 135 patients who entered the extension phase of dosing. We have now data on those 135 patients including 85 patients at week 96.

Through that time, we have developed--we have seen two more patients that developed the K65R. So the rate remains very low with extended dosing.

DR. STANLEY: Then my last question, for either the FDA or the sponsor. What are you defining--the approval has been requested for treatment in HIV-infected adults. What is the definition of age cutoff for adults that now we are using; thirteen or eighteen?

DR. STRUBLE: Eighteen.

DR. GULICK: Dr. Hamilton and then Dr. Tebas.

DR. HAMILTON: I have a number of questions and a few points of clarification, particularly regarding the efficacy summary slide on Page 50 of the handout. Since the efficacy summary is often the only thing that people remember, I think it is important to know what each of those points represents.

So please tell me if I am mistaken here. It says, on the first point, tenofovir monotherapy for 28 days resulted in a 1.2 log copy ml change from baseline. Unless I am mistaken, that is based on six patients in Study 901 at the 300 milligram dose; is that correct?

DR. TOOLE: That's correct.

DR. HAMILTON: So, really, a more representative change would be those values reflected in 902 and 907 which are more like 0.5 and 0.6.

DR. TOOLE: That's correct except it is important to remember that 902 and 907 were intensification designs in which tenofovir was added as a single agent to a single baseline regimen whereas Study 901 was monotherapy for twenty consecutive days. So the 1.2 log reduction was observed as monotherapy.

DR. HAMILTON: Secondly, in the subgroup analysis of those who fell by 450 copies per milliliter on Page 35 of the handout, those data are at 24 weeks; is that correct?

DR. TOOLE: That is the time-weighted average change from baseline to Week 24.

DR. HAMILTON: So that relates, then, to the last point, the final point, which says benefits are durable through 48 weeks. Have I just missed the 48-week data?

DR. TOOLE: That comes from Study 902. If I could have Slide 622, please.

[Slide.]

For the 300 milligram dose group, the plot of the mean change from baseline at Week 24, we saw a 0.6 log reduction. However, that was maintained out through Week 48 and that is where the durability to 48 weeks comes from.

DR. GULICK: May I remind committee members to speak into the mikes because people may be having trouble hearing.

Dr. Tebas and then Dr. Munk.

DR. TEBAS: I would like to ask you a couple of questions about your study that you didn't present, and I have seen the results on Page 15 of the FDA summary. Can you tell us more about how those patients were selected? These were done at multiple sites or only one site? Was there a central reading for these or it was the reading at the site?

And, two, it seems as if you did between-arms comparison. You compared placebo with the tenofovir arm. Did you do a within-arms comparison? Did you compare the people that were randomized to tenofovir, the Week 24 to the baseline, because I don't think you have power to detect differences with placebo but maybe you have more power to detect differences within the same arm.

DR. TOOLE: The BMB substudy was done at multiple sites in both studies, 902 and 907. We concluded, and the FDA has also concluded, that there was no apparent dose response, so no dose response between the arms, between the different tenofovir dose groups. That was through 48 weeks of dosing.

After 48 weeks, all those patients in the substudy were receiving 300 milligrams.

DR. TEBAS: Was it a reading of--

DR. TOOLE: I'm sorry; that was a central location.

DR. TEBAS: Did you do a within-arms comparison?

DR. TOOLE: No; again, we didn't do that comparison but there was no apparent dose rsponse. In fact, the median change, after Week 24, was greatest in placebo. It was a -2 percent. Through Week 48, none of the treatment group showed a change greater than that.

DR. TEBAS: Say it again?

DR. TOOLE: The median change in bone-marrow density observed in Study in 902 at Week 24 was -2 percent. Through 48 weeks, all the doses showed a change which was less than that observed in placebo.

DR. TEBAS: Here in the placebo arm, the data on the table I see says the median change, 0.9 percent in the placebo arm increase and the tenofovir arm -0.7 percent decrease.

DR. TOOLE: Those are the data for studies 902 and 907.

DR. TEBAS: This is Page 15 in the FDA folder. In this folder, there is nothing on--

DR. GULICK: Which slide is that? Perhaps we could have that slide?

DR. STRUBLE: What he is talking about is just this data in 902. We pooled the data from 902 and 907 so the exact percentages wouldn't be the same. So this is based on the pooled data whereas Dr. Toole is talking about what he saw in Study 902 alone.

DR. TEBAS: I see. Okay.

DR. GULICK: Dr. Munk?

DR. GULICK: Dr. Munk.

DR. MUNK: I am trying to get a little more understanding of the patient populations in 902 and 907. In 902, do you know how many patients had a viral load higher than 50,000?

DR. TOOLE: I don't know offhand, no. If your question is leading towards do we have activity in patients with higher viral load, the answer is yes, we have done that analysis.

DR. MUNK: Where is that?

DR. TOOLE: 388, please.

[Slide.]

We looked and saw the tenofovir had activity in patients who had the highest quartile baseline viral loads, and this was in Study 902.

There were 20 patients randomized to the placebo group, and those 7 patients in the highest quartile with baseline viral loads had a mean baseline viral load of around 44,000.

For the 54 patients that were randomized to the 300 mg dose group, the highest quartile for those 14 patients, the mean baseline viral load was 76,000 copies per mL. The DAVG24 shows that there was little change in placebo and approximately a 0.5 log reduction in the tenofovir group. This is for the 300 mg.

DR. MUNK: And for the patients in those studies, you showed us the average length of time on antiviral treatment. Do you have information on the average number of previous agents that they had been exposed to?

DR. TOOLE: We just sorted that out by either greater than 4 or less than 4. I can find that data. I don't have those offhand. Most patients had at least 4 agents prior to therapy, but I don't know the exact percentages.

DR. MUNK: And did you collect any information on adherence?

DR. TOOLE: No, we did not.

DR. GULICK: Dr. Johnson.

DR. JOHNSON: I am going to extend on those questions just to get a better understanding of the likelihood of finding a lot of resistance at baseline.

In your Study 902, you gave us, in the demographics, the median years prior ART experience. Could you comment on, for example, median number of prior regimens, which might get to how many sequences of agents patients had rolled through, and secondly, although the statement is made for both of those studies, 902 and 907, that baseline genotypic analysis revealed that 94 percent had one or more nucleoside-associated RT mutations, do you know how many were in the category of 2 or more, or 3 or 4 or more? I mean just 1 could be just a K70R that we might not care about, for example.

I am just trying to get at how much, what percentage of these patients at entry had lots of prior regimens and their history, and lots of baseline RT mutations.

DR. TOOLE: We didn't collect the data on exact number of prior regimens these patients have been exposed to, just on when they first started receiving antiretroviral treatment. With regard to the number of mutations at baseline, I will let Dr. Michael Miller, our virologist at Gilead Sciences, address that question.

DR. MILLER: Michael Miller Gilead Sciences. Can I have Slide 336, please.

[Slide.]

So, basically, in answer to your question, the exact number of baseline nucleoside-associated mutations was around 3.5, and I don't have the distribution of the actual baseline number, but I have the distribution, which you can kind of infer from looking at the distribution here of patients with no TAMs, or one or two TAMs, or three TAMs, or greater than and equal to four TAMs, and you can get a feeling from those n's in parentheses there where the n, the average was around 3 to 3.5, in that region, you get the mean or the median, and there was no appreciable difference between the active and placebo arms.

The specific types of mutations, can I have Slide 616, please.

[Slide.]

Try 516.

[Slide.]

Just in terms of the definitions that we employed, these were the resistance collaborative group definitions, and the specific nucleoside-associated mutations are listed here. There were 16 of them. The ones in yellow are the ones that are thymidine analogue mutations according to our protocol. So, these are the mutations that we were actually counting in the analyses, as well as for the primary NNRTI and the PIs, as well.

DR. JOHNSON: Could I ask two more questions while you are up there? Could you just for information tell us what method of genotyping was used and where it was done?

DR. MILLER: Yes. In Study 907, we used exclusively Virco Laboratories for both the genotypic and phenotypic analyses, and their genotyping then goes out to amino acid 400, and that is population based analyses.

In Study 902, we used Virco for the phenotypic data, but we used Visible Genetics for the genotypic data, and they have a more limited amplimer going out to amino acid 250 for all of those patients.

DR. JOHNSON: And do you know at each of those two laboratories, were phylogenetic sequence analyses for quality assurance, that each of these sequences was distinct from each patient analyzed at baseline or over time?

DR. MUNK: We did do quality control throughout the process. This was a blinded analysis in terms of treatment, but it was not blinded in terms of patient I.D.'s, and since we had follow-up samples from all patients, any discrepancies which were noted were then pursued to determine whether or not there was an error in the sequence analysis or not, and all of those were kind of feted out and metted out, and confirmed.

DR. JOHNSON: Finally, with regard to phenotyping, in the Study 907, there is a comment that only 85 phenotypes were presumably amplifiable out of 137 baseline samples. Was this reflecting that these were specimens, their sensitivity, 1,000 copies from, because these patients were entering the study with a lower viral load?

DR. MILLER: Yes, exactly.

DR. JOHNSON: And have you ever looked at the virologic assay in parallel with the Virco assay in any of your phenotypic analyses?

DR. MILLER: No, we have never done that head to head comparison. I think both of the companies are improving their assays, but indeed, from studying 907, the attrition between the value of 85 and the intended value of 137 was done was due to low viral loads.

We sent them actually every sample, and they tried, and the failure rate between 50 and 1,000 was very high.

DR. JOHNSON: Was that with the older form of the Virco assay or the new and improved, do you know?

DR. MILLER: That was with the older form. I don't believe they have actually rolled out for commercial purposes the new form.

DR. JOHNSON: Thank you.

DR. GULICK: Just to let the committee know, I am going to call on people who haven't had the chance to ask questions, and then I will come back to people for additional questions.

Dr. Sun and then Dr. Yogev.

DR. SUN: Just a couple questions. One is technical, methodologic. In your in vitro studies that are cell based, such as virology and some of the safety pharmacology work, are you using tenofovir or tenofovir DF?

DR. TOOLE: DF.

DR. SUN: Is that consistent across in vitro studies, because of the increased permeability?

DR. TOOLE: We do see approximately 100-fold increase in the potency of tenofovir when we go from comparing tenofovir to tenofovir DF, presumably because we are getting more drug in the cells.

DR. SUN: A second question relates to 907. I think one of your prespecified stratifications was on number of antiretroviral drugs at baseline. I think it is 4 or fewer and greater than 4.

Do you have that analysis because I didn't see that in the briefing package?

DR. TOOLE: That analysis was done by the FDA. That was not one of our prospectively defined subgroup analyses in Study 907.

DR. SUN: But you stratified on that basis, right?

DR. TOOLE: No, we stratified on the basis of HIV RNA less than or greater than 5,000 or CD4 counts less than or greater than 350.

DR. SUN: I am looking at page 31 of the briefing document where it says patients were stratified to viral load, as you say, CD greater or less than 200 and number of ART drugs prior to study entry.

DR. TOOLE: I will have to go and check the protocol because it is my understanding that was not part of this. There were two stratifications.

DR. GULICK: Dr. Yogev.

DR. YOGEV: In Study 907, how many patients were more than 5,000 viral load, and how many of them were less than 400 at week 24?

DR. TOOLE: In Study 907, for the numbers of patients that had baseline viral loads greater than 5,000, was 99 in the treatment group, and I believe it was 43 in the active group. The percentage of patients that had viral loads less than 400 copies/mL at week 24 was 45 percent in the tenofovir arm and 13 percent in the placebo arm.

DR. YOGEV: That is the number you give for the whole group. Is it the same for greater than 5,000? I am asking specifically for greater than 5,000.

DR. TOOLE: I don't have that. I am sure it is less, but I don't have the exact numbers. It is important to point out, though, that this was an intensification study, and patients who had greater than 5,000 copies/mL, in order for them to reach the less than 400 copies/mL, you are asking for a 1 log change, and there was, I think offhand, there was probably around 10 to 20 percent of patients who had a 1 log change, so I am sure it is less than the overall group, but again, it is the difficulty of achieving that, the addition of one drug to a stable background regimen.

DR. YOGEV: The main reason why I am asking is when you are asking for naive patient, not too many of us will start in less than 5,000 therapy, I am sure you are familiar, and then your recommendation is 55,000, so one would like to see how it would work there.

Also, I noticed that in your submission, you find a synergy between this drug and AZT and amprenavir. How many of the patients in your studies were on those drugs as the backbone versus other drugs, which you didn't find synergy in vitro, did you compare between those?

DR. TOOLE: No, we didn't do that analysis, but a large number of patients were also receiving AZT concomitantly, very few were receiving amprenavir.

DR. YOGEV: I noticed in 907, if you did it, CD4, less than 200 patients, did very well against the placebo, but comparatively to those who had more than 200, didn't do that well.

Did you have any analysis, is that minus 4, minus 6, and 5, is there a statistically significant difference between the two?

DR. TOOLE: Yes, that difference is highly statistically significant.

DR. YOGEV: Not with the placebo, between themselves.

DR. TOOLE: We didn't do that comparison, however, it is important to point out that the FDA has recently conducted an analysis and discovered that part of that reason that we see less response in various subgroups has to do with baseline TAM expression, which is a confounding variable, and we have only discovered recently that the TAMs can diminish treatment response with tenofovir.

DR. YOGEV: So, would you suggest in those who have less than 200, have more TAM resistance?

DR. TOOLE: Correct.

DR. YOGEV: Can we have some analysis of with and without TAM, less than 200, because it is a population that is unique, and the response is the lowest that you have, so it would be interesting to see if that is really the reason, which might be, or the other just affecting it, because one thing which impressed me is the CD4 response is not as one would expect to see.

The last question, in the pediatric population, your age will be from what to what?

DR. TOOLE: Our Phase III study will be conducted in children age 6 months to 17 years.

DR. YOGEV: Six months to 17 years.

DR. TOOLE: Yes.

DR. YOGEV: And you are going to subgrade them, and it will be less than 2 years, above 2 years--

DR. TOOLE: That protocol is still under development, but we will plan something like that.

DR. YOGEV: For the FDA, the safety summary, you pulled out the diarrhea and the rest, is there more of them in tenofovir by percentage, is that statistically significant?

DR. STRUBLE: Only for vomiting, and that is all grades, Grade 1 through Grade 4.

DR. GULICK: Dr. Wood.

DR. WOOD: I had a question regarding the safety analysis about bone changes specifically. Was the substudy analysis done in women? Between 902 and 907, there are only 96 females in this study.

My concern is about differences that may occur in terms of risk for changes in bone mineral density based on sex. Was that kind of analysis done?

DR. TOOLE: No, that was not done. Again, there were only 74 patients in the bone mineral density substudy in Studies 902 and 907. We expect to be able to do that in Study 903, where we will have all 600 patients being followed serially for BMD changes.

DR. WOOD: Another question regarding HIV RNA results according to demographic baseline and characteristic, and maybe somebody from the FDA might address this question, but there were several significant treatment interactions that were documented.

The most important were that there was lower response to tenofovir with greater than 5,000 copies/mL, and also with greater than 4 drugs.

What I wanted to know, is there any way those two factors can be combined and examined in an analysis together, so that we would know what the response would be for someone who had greater than 5,000 copies/mL and had greater than 4 antiretroviral drugs in terms of past antiretroviral treatment?

DR. STRUBLE: We could look at that, but what we found is that subsequently to sending out the background, we did some other analysis looking at baseline viral load and prior antiretroviral use, and the baseline genotype, and found that those interactions went away, that they were no longer significant, that it was the presence of key mutations, specifically the 41 and 210, that affected response, and not necessarily the baseline viral load.

DR. WOOD: This is a virology question. I am not sure whether or not it was both in 902 or 907, but there was a report of the K65R genotypic mutation in six patients, but then there was also a report of a greater than 4-fold phenotypic resistance in nine patients, and I am just curious as to what the explanation is of the virologist for the phenotypic resistance in two tenofovir in the setting of a lack of a genotypic mutation.

DR. TOOLE: There were six patients whose HIV expressed a K65R mutation at baseline. Importantly, not all of those patients had more than a 4-fold increase in susceptibility or decrease in susceptibility to tenofovir. It is generally in the range of 3- to 4-fold. So, not all those would be necessarily included when we looked at the 4-fold increase in baseline tenofovir susceptibility.

DR. SCHAPIRO: Could we see the ones, the genotypes of that, the patients you are alluding to?

DR. TOOLE: I will let Dr. Michael Miller address that question.

DR. MILLER: I don't have a specific slide showing the individual genotypes. That actually was in our study report. However, what we found is a high fraction, almost all of the patients, in fact, had both the 41L and 210W TAM. A couple of patients have the K65R, and we also had one patient who had the 269 insertion mutation, but the overwhelming dominance of greater than 4-fold reduced susceptibility appears to be due to the presence of substantial numbers of thymidine analogue mutations inclusive of 41 and 210. DR. GULICK: I would like to give the opportunity for any committee members who haven't had the chance to ask questions.

Dr. DeGruttola.

DR. DeGRUTTOLA: I have two quick questions. For the patients who went below 50 or below levels of detection for the calculation of the DAVG, did you just use the level of detection as the value for calculation of the primary endpoints?

DR. TOOLE: We used 50. We used the ultrasensitive assays, 50 was used for the lower limit.

DR. DeGRUTTOLA: I had a question about actually in the report, there is a Table 419 that gives responses by baseline resistance mutations in Study 907, and you break out the response for tenofovir versus placebo for some of the TAMs and some combinations like the 215 and 184, but not for others like the 210 and 41, so I was just curious how it was chosen, which categories to break out in that table, which TAMs to show the effects separately or combinations of those.

DR. TOOLE: This is the FDA's table?

DR. DeGRUTTOLA: This is Table 419 from the Gilead report on page 51.

DR. TOOLE: Okay. I will let Dr. Miller again address that question.

DR. MILLER: Perhaps we can have Slide 87. I believe this is the one you are referring to.

[Slide.]

Basically, we have protocol-specified mutations, which we were to analyze, and then there were exploratory analyses done, so the presentations and all of the tables that were in the Gilead of background information were from the protocol-specified genotypic groupings, and these included the presence or the absence of the M184V mutation, the presence of absence of the thymidine analogue mutations, as well as, on the next slide, the presence or absence of the 215Y mutation.

[Slide.]

The other one, 69L74V and K65R, we included. They were listed in the protocol as being exploratory because we knew that they would be unlikely to be a large number of patients in those groups. Then, the additional exploratory analyses that came subsequent to that specifically looked at the patterns of thymidine analogue mutations, breaking out those six mutations specifically.

DR. DeGRUTTOLA: I see. So, then, 210 and 41 weren't mentioned in the protocol, but you found out subsequently in the exploratory analysis.

DR. MILLER: Exactly.

DR. DeGRUTTOLA: Thank you.

DR. GULICK: Dr. Dorsky.

DR. DORSKY: I had a number of questions related to safety. Were there any subgroup analyses of patients who might be heavy alcohol consumers or have had chronic diarrhea or other conditions which might predispose to phosphate wasting?

DR. TOOLE: No, we did not do any subgroup analyses looking at that.

DR. GULICK: Before I turn to going back to people, I had a couple questions myself. Was phosphate supplementation permitted and/or encouraged on these studies?

DR. TOOLE: Yes, it was, and in the 687 patients that received a 300 mg dose, there were 17 patients who received phosphate supplementation. In general, those were the patients who had the Grade 2 or higher abnormalities.

DR. GULICK: So, it was at the discretion of their primary physician whether to add it.

DR. TOOLE: True.

DR. GULICK: Did the protocol recommend phosphate supplementation?

DR. TOOLE: In the event of a Grade 2 or higher abnormality. It did not specify, but it recommended phosphate supplementation.

DR. GULICK: You showed us the intent-to-treat analysis and then an as-treated analysis for Study 902 to try to address the fact that a certain number of people actually changed their background medications.

Do you have the as-treated analysis for Study 907 also? I don't recall seeing that.

DR. TOOLE: I didn't show it because the as-treated analysis for Study 907 is almost exactly the same as the intent-to-treat analysis, because again, there were so few patients who changed their background regimens during the course of the first 24 weeks compared to Study 902.

DR. GULICK: We found on ACTG359 a significant PK interaction with adefovir and saquinavir that has never been fully explained.

Was an interaction between tenofovir and saquinavir formally looked at?

DR. TOOLE: We did not look at saquinavir. We chose the two protease inhibitors indinavir and the lopinavir/ritonavir combination. We did not see an interaction with indinavir.

DR. GULICK: In the background materials, it talks about some of the ways that you are proposing to look at long-term safety. One of them is to look at the expanded access program over time.

Could you tell us what the commitment is to follow patients on the expanded access programs, let's say, after the drug is approved?

DR. TOOLE: Most of our safety follow-up is going to come from Study 910. In that study, we enrolled 575 patients who were previously randomized in the Studies 901, 902, and 907. Those patients will be followed until December of 2002, at which time we will have over two years of follow-up and more than 450 patients.

We are not going to sort out any patients in the expanded access population that will be followed separately from the rest of the other patients.

DR. GULICK: Lastly, in vitro, the presence of an M184V mutation is associated with an increased virologic effect, but apparently didn't see this clinically. Do you have a reason why that might be?

DR. TOOLE: Actually, in the absence of TAMs, the M184V was associated with a significant increase in tenofovir, in the DAVG24, however, approximately 70 percent of patients in our studies were also expressing TAMs, and in that broader population M184V made no difference.

DR. GULICK: Thank you.

I am going to go back to a couple of people. Was that a follow-up, Vicki? Yes. Dr. Johnson.

DR. JOHNSON: You can call me Vicki.

[Laughter.]

In the first slide that Dr. Miller went up and showed, that gets to Chips, Trips--I am sorry--

DR. GULICK: You can call me Dr. Gulick.

[Laughter.]

DR. JOHNSON: Table 419, back on this M184V effect, this best reduction of 0.97 logs compared to all patients at 0.59, the p-values presented for heaving M184V alone versus placebo, what is the p-value for having M184V versus the all-patient group?

Could you just go back over that, because I think it gets to the question do clinicians need to keep their patients on 3TC or not, if they are treatment-experienced, knowing that, as you have just said, 70 percent have one TAMs that sort of negates this effect.

DR. TOOLE: The analysis, which did show a statistically significant effect with the presence of the M184V, was in the absence of TAMs, and that p-value was 0.03. In the presence of other TAMs, the effect was not statistically significant.

DR. JOHNSON: So, what would be your recommendation with regard to--maybe we will discuss this later--indication, should clinicians keep their patients on 3TC to get this effect?

For treatment-experienced patients, it seems that the continuation of 3TC is not required.

DR. GULICK: We may want to address that in the afternoon some more.

I am going to go back to some people who asked to ask some more questions.

Dr. Bone.

DR. BONE: Thank you. I do have several additional questions. We talked earlier about the available histological information from the monkey studies, that you have necropsy data from your dog and rodent studies, I believe, and you saw the histologic abnormalities that were similar at the higher doses.

Did you find no-effect dose for the osteomalacia changes in dogs or rats?

DR. TOOLE: I will let Dr. Bischofberger address that question.

DR. BISCHOFBERGER: I would like to clarify something first. The monkey, at the 10 mg/kg dose, 4-fold the human exposure. You are correct, we don't have any histological no-dose effect, but those animals did not have any hypophosphatemia, no glucosuria, no proteinuria, and all those three things were present at the higher dose.

So, with regards to the rats and dogs, we do have no-dose effects. In each case, they were at the lower dose than the one that showed the abnormalities.

DR. BONE: What multiple of the human dose?

DR. BISCHOFBERGER: In the dog, we saw bone abnormalities at 30 mg/kilo. That is 10-fold the human exposure. The next lower dose that was used was 10, so it's one-third of that.

In the rat we saw bone abnormalities at 1,000 mg/kilo, which is about 20-fold the human exposure. At the next lower dose, the 300 mg, we saw minuscule, but statistically significant changes, and at the 100 mg/kg we saw, that was the no-effect level with regards to bone abnormalities.

DR. BONE: How well did the histologic or did you formally analyze the relationship between histologic abnormalities and the clinically observable information, such as serum phosphorus levels?

DR. BISCHOFBERGER: You mean did we do correlations?

DR. BONE: Yes.

DR. BISCHOFBERGER: No. You have to understand the first observation of bone abnormalities was in these monkey efficacy studies, which were done at the University, so it wasn't even done at Gilead, and they were not toxicology or GLP studies.

Only once we became aware of those effects, we instituted in our then ongoing chronic tox studies, bone monitoring, so in many cases, the baselines were actually not here. The effects were really small that we saw.

I also want to comment on Dr. Farrelly presented the PTH was up. That is, in general, true, but the data were highly variable. I think if you had to guess overall, you would say PTH would trend up, but there was no dose response, and it was statistically significant only at certain time points, and not at others.

DR. BONE: Did you do tetracycline labeling at the end of study for the dogs and rats in order to do formal histomorphometry on necropsy?

DR. BISCHOFBERGER: No, we did not, not in those studies.

DR. BONE: Did you obtain samples that could be assayed for 1,25-dihydroxy vitamin D when the animals were sacrificed?

DR. BISCHOFBERGER: We did assay for 1,25-dihydroxy vitamin D, but again, the data were variable, and I would say overall there was no change neither statistically nor even numerically.

DR. BONE: We saw that the dog did show, although the exact numbers weren't given, the 1,25 was low. I guess I would be interested in seeing the actual data presented for the rat and any human or dog data that you have for the 1,25 dihydroxy D, rather than just having a general statement, if we could do that.

DR. BISCHOFBERGER: I don't have a slide with me, but I can certainly get those data to you today.

DR. BONE: Thank you. The other question, a couple more questions, do we have any information about magnesium status in either the animal or human studies?

DR. BISCHOFBERGER: We looked at magnesium in the animals, but there were no changes in serum magnesium.

DR. BONE: You just measured total serum magnesium levels?

DR. BISCHOFBERGER: That's right.

DR. BONE: You didn't do anything else.

DR. BISCHOFBERGER: No.

DR. BONE: That is not very sensitive. Okay.

In the BMD studies that you have performed, it looked as though you had some mostly lumbar spine studies and a few femurs. Do you have any measurements in predominantly cortical areas, such as the forearm?

DR. TOOLE: No. We measured BMD changes in the spine and hip in Study 907, and in Study 902, just the spine.

DR. BONE: But no cortical, no measurements from forearms, for example?

DR. TOOLE: That is correct. Is Dr. Genant available?

DR. BONE: The reason I ask is it tends to be, particularly the ones at radial site, has a much higher proportion of cortical bone, which is where you described your histologic abnormality.

I think that is all my questions for the moment.

DR. GULICK: I had forgotten, unfortunately, Dr. Lukert, who has been patiently listening. Again, I am not sure she can speak to us. If you can, we would be happy to entertain your questions, and I apologize for overlooking you.

She can't right now. Okay. Thanks.

Dr. Pomerantz.

DR. POMERANTZ: Two questions. One of them, clinical, I want to extend Dr. Wood's question from the past about looking at subgroups. Clearly, there are people now on HAART that have inagnatic [?] osteonecrosis and also those that are on chronic steroids. The committee, I am sure, is going to be getting more into small groups of people, if the drug goes into the community, that may be hurt by this.

Do you have any data on those groups or even anecdotal data in the large number of patients with problems with fractures or such, do you see anything or do you have any data on people who are on steroids who have the HAART-associated osteonecrosis?

DR. TOOLE: There was one patient on the study that, before entering the study, had a history of avascular necrosis, and this patient had a total hip replacement, and one month after had a fall and fractured his femoral neck. That is the only one we had.

DR. POMERANTZ: And none of these people were on chronic steroid use of any type?

DR. TOOLE: I don't recall the patient's history, I don't believe he was, though.

DR. POMERANTZ: The second one if more virological. We talked a little bit about the high-end research. I was interested in the low end in residual disease, and you had a number of people that went undetectable as defined by less than 400 and then more stringently less than 50.

There is some question in the durability of those effects based on different drug combinations. What I am referring to is the blips or spikes that can take place in some of those patients.

Doug Richmond feels that if there is no effect on short-term mortality and morbidity, there is some data from other groups that that may not be the case.

Did you monitor those people who went to less than 50 or less than 400 over your year studies to look for blips of spikes back in the detectable range?

DR. TOOLE: We didn't do that. I think the FDA presented the graph representing those changes to less than 50 or 400, but predominantly, those patients who achieved less than 50 or 400, those changes were variable [?], certainly through the course of 24 weeks.

DR. POMERANTZ: So, during that time when you monitored these people, you had no patients that blipped or spiked?

DR. TOOLE: There may have been a few patients, but there weren't enough patients that would require any--

DR. POMERANTZ: Okay. Thank you.

DR. GULICK: Any other questions from the committee? Dr. Yogev.

DR. YOGEV: I was intrigued by your in vitro data, that there is almost a 10-fold increase in IC50 for the PBMC, the mononuclear cells versus the MT2, and then also dendritic macrophages, and I couldn't find what was the IC50 for those.

DR. TOOLE: I will let Dr. Bischofberger address that question.

DR. BISCHOFBERGER: The qualitative answer is that the tenofovir is more potent in general in macrophages than it is in lymphocytes.

DR. JOHNSON: Is he asking why the IC50 is higher in the MT2 cell assay?

DR. BISCHOFBERGER: If I could get 409.

DR. JOHNSON: It is a viral cytopathic effect assay. It would require higher concentrations.

DR. BISCHOFBERGER: Reproducible, the question that you asked.

[Slide.]

This shows anti-HIV activity in MT2 cells and PBMCs, and in monocytes, macrophages, and you see that the IC50 is 0.4 versus 0.63, and MT2 is 0.12 and PBMCs, and that is consistent with the fact that macrophages are, in general, resting cells. They need thymidine kinase to activate nucleosides. Tenofovir is a nucleotide, and doesn't have to undergo that activation pathway.

DR. POMERANTZ: Just a comment on that because I think that is good point, but if you had done that in initially quiescent PBMCs, as some groups have, you might have seen it closer to what you see in macrophage monocytes.

DR. BISCHOFBERGER: That is exactly right.

DR. POMERANTZ: And then hit them with PHA and IL-2 after they have seen the drug for a couple of days, you might had a different effect.

DR. BISCHOFBERGER: That was actually a study that was published in PNES by Imbach and colleagues, and they found exactly that. Thank you.

DR. YOGEV: The second question, the hydroxyurea addition, amazingly almost 20 to 30 times more activity of tenofovir, and then you claim in 901, you didn't see it when you use it only on 75 mg, and when you look at the data with the small number that you have, it is almost double the amount of viral load decrease from 0.22 to 0.44, something like that.

Do you feel comfortable that it really didn't approve itself clinically or because of the low number and using the lower dose, you did not pursue correctly this?

DR. TOOLE: I think the change that we saw in the 75 mg cohort that received either no hydroxyurea or hydroxyurea concomitantly didn't warrant further evaluation when we consider the changes that we observed in the 300 mg dose group.

DR. YOGEV: By itself.

DR. TOOLE: Did not.

DR. YOGEV: By itself, but you did not use hydroxyurea with 300 mg?

DR. TOOLE: Correct, we did not.

DR. GULICK: Dr. Schapiro.

DR. SCHAPIRO: One question is just regarding the 907, why was it limited to 10,000 copies?

DR. TOOLE: We wanted to prevent the corruption of the primary efficacy endpoint by a lot of background switching. In Study 902, we allowed patients to enroll with viral loads up to 100,000, but in that study, about 30 percent of patients changed their background regimen during the course of the first 24 weeks in an effort to minimize that switching and also to make it more amenable to investigators and their patients who may be randomized to placebo for 24 weeks, we restricted the upper viral loads limit to 10,000 copies.

DR. SCHAPIRO: And the other question, I don't think we saw the correlations between the TAMs and the phenotypic changes. Do we actually have it? On the Virco study, there are 20 such patients, and there were others in the additional studies. That data which we usually see, which shows these mutations to this fold change, we didn't actually see those, we just saw data which shows it as a group.

What we usually look at is we see various accumulations of TAMs and what they do. Do you have that type of data?

DR. TOOLE: I will let again Dr. Miller address that.

DR. MILLER: May we have Slide 75, please.

[Slide.]

These are the results then looking at the specific number of TAMs, just the aggregate out of the 6 and the baseline, and the susceptibility to both tenofovir and zidovudine. As you can see that, 110, the susceptibility to tenofovir is 0.8, and it looks like it is increasing with increasing numbers of TAMs, greater than or equal to 4, there is reduced susceptibility of 2.8-fold to tenofovir.

In contrast, the zidovudine levels are notable even at just 2 TAMs, increasing up to 19-fold resistance.

Perhaps more interesting is from Slide 360.

[Slide.]

It is looking at the specific patients in the integrated analysis of Studies 902 and 907 for whom we had baseline phenotypic data, and this is then the same stratification by number of TAMs, presence or absence of the M41L and L210W mutations.

If you just look at the far right column, you can see no TAMs, and then one or two TAMs, three or four TAMs, showing a decreased susceptibility up to 2.6-fold, and then when you stratify based on the presence or absence of the 41L, the 210W, you go from 2.8-fold reduced susceptibility to 1.7-fold in the absence of the 41 or 210W.

So, the results appear very consistent between the genotypic and phenotypic, and the clinical trial results.

DR. SCHAPIRO: You don't have though actually, as you were saying here before you wanted for the 210, you don't actually have the genotypes with the phenotypes for these.

You are just sort of lumping the TAMs together and then showing us the analysis. You don't actually have the data that shows the genotypes and the phenotypic correlate--actually, in that last slide you showed--

DR. MILLER: The last slide, I think the last two lines of the last slide. We can show that again.

DR. SCHAPIRO: Could we see the last slide again?

DR. MILLER: 360.

[Slide.]

DR. SCHAPIRO: The three TAMs plus, that can be anywhere from three to six mutations, and the one below it can only be three or four mutations. So, that is a little bit of a biased analysis since we know that accumulation also affects it.

You are only allowing the maximum TAMs you can have is four, if you don't have four, you wanted 210, whereas, in the line above it, it can be up to six.

DR. MILLER: The mean number is very similar actually. I don't have the actual number because as you might be aware, there are specific patterns of mutations, and they tend to top out at around three or four, and we rarely have five or six mutations actually in any individual patient. We have not done the specific, I think analysis, you are referring to is simply to add the 41 or 210 mutation in the context of a site-directed recombinant virus or something like that.

This is very new information for us. It is a pleasure to discover in these exploratory analyses, and we will be following up on that certainly.

DR. GULICK: If there are no other burning questions at this point from the committee, why don't we stop here. It is 12:15. We will break for lunch until 1:10, at which time we will resume.

Thank you, everyone for a good morning.

[Whereupon, at 12:15 p.m., the proceedings were recessed, to be resumed at 1:10 p.m.]

AFTERNOON PROCEEDINGS

[1:25 p.m.]

DR. GULICK: We want to do a couple of things in follow-up to the morning.

Dr. Lukert, can you hear us? I will take that as a no. I wanted to give her the opportunity to ask any questions, and she didn't get that opportunity this morning. We will see if she gets back on in the next minute or so.

We wanted to give the sponsor an opportunity to follow up on some of the questions and points that were raised this morning. I see Dr. Bone joining us.

DR. TOOLE: First of all, with regard to an earlier question, looking at the DAVG24 in Study 907, with regard to patients who had more than or less than four previous antiretroviral agents, for those patients who had more than four prior agents, the change in the placebo group was minus 0.2, and the change in the tenofovir group was minus 0.56 log reduction, and that difference was highly statistically significant.

Secondly, regarding Dr. Yogev's question, were the percent of patients that went below 400 copies/mL, who enrolled in Study 907, with baseline viral loads greater than 5,000, there was zero in the placebo, and 15 percent of patients in the tenofovir arm, and that was significant with a p-value of 0.008.

Dr. Bone, regarding your question of cortical bone mineral density, I would now like to invite Dr. Harry Genant to join us to telecon. Dr. Genant is Professor of Radiology, Epidemiology, Medicine, and Orthopedic Surgery, and Executive Director of the Osteoporosis and Arthritis Research Group with the University of California at San Francisco.

He has also chaired and published recommendations from a World Health Organization-sponsored task force on osteoporosis.

Dr. Genant.

DR. GENANT: [By telephone] Good afternoon. Are you able to hear me?

DR. GULICK: Yes.

DR. GENANT: Fine. Dr. Bone asked the question with regard to measurement of a cortical bone site, such as the forearm, and that is an important question. In the two pilot analyses that were done in 902 and 907, forearm was not measured, but the spine was measured in 902 and 907, and the hip was measured in 907, as well.

Of course those are the two most important anatomic sites, and from the hip itself, one can generate information that is relevant to cortical bone, particularly in the total hip measurement, but at that site, given the numbers of patients studied, there were no significant changes.

DR. BONE: Harry, this is Henry. How are you?

DR. GENANT: I am doing fine, thank you.

DR. BONE: Good. Wouldn't you think that going forward, the forearm would be something that ought to be looked at as we go along?

DR. GENANT: Yes, I think that if one does begin to see significant changes at the spine and/or hip, that the forearm, as a measure of non-weight-bearing cortical bone, would be of interest.

I do believe that from the hip measurement itself, one can extract a purely cortical measurement from the sub-trochanteric area that will give essentially a cortical measurement, although it is a non-standard technique.

DR. BONE: I don't think any of the standard instruments would give that as one of the standard readings.

DR. GENANT: That is correct, although it can be extracted from the routine acquisitions.

DR. TOOLE: Can I suggest that we will pursue this also in the questions for the committee.

Dr. Bone, regarding your question that we are observing small changes in the fractional secretion of phosphorus and how do those translate in changes in serum phosphorus, if I could have Slide 255, please.

[Slide.]

Shown here are the median changes from baseline in serum phosphorus measured for the placebo group and the tenofovir 300 mg group in Studies 902 and 907. Through week 24, there was no significant differences in the serum phosphorus level between placebo and tenofovir 300 mg group.

With regard to your question of how many patients had changes of 0.5 mg/deciliter or more, that would be corresponding to here. Whenever those changes occurred, they occurred in a similar number of patients in the placebo group and the tenofovir group.

DR. BONE: I am sorry. Could you go back?

DR. TOOLE: This is the median and the interquartile range. So, 25 percent of patients had a change of 0.5 mg/deciliter or more in serum phosphorus, however, these changes were similar in the placebo group and the tenofovir group.

Slide 254, please.

[Slide.]

This now looks at the long-term data following patients out for more than two years, and again, the changes that were observed over two years were consistent with what was observed in the course of the first 24 weeks.

DR. BONE: Again, what you are showing here is the median changes. What about the patients who showed a small change, small decline?

DR. TOOLE: These are medians with the interquartiles, so the patients who had a change of a decrease of 0.5 mg/deciliter or more would be the lowest 25 percent of the patients, however, 25 percent of the patients in the placebo group also had a similar change during the first 24 weeks of the studies.

DR. BONE: Thank you.

DR. TOOLE: Lastly, I would like to invite our consultant Dr. Steve Teitelbaum. Dr. Teitelbaum is the Wilmer and Roswell Messing Professor of Pathology and Immunology at Washington University School of Medicine in St. Louis. He is Chairman of the Institutional Review Board at Barnes Jewish Hospital and the past President of the American Society for Bone and Mineral Research.

DR. LUKERT: I would like to ask a question about the phosphate supplement. When you started phosphate supplements, did you start after the first abnormal phosphorus or after the second abnormal serum phosphorus?

DR. TOOLE: That was variable. There were 62 patients who had Grade 2 or higher hypophosphatemia. Among those 62 patients, 11 used phosphate supplementation at the onset of the hypophosphatemia.

DR. LUKERT: Did they just correct, or what happened to their serum phosphorus?

DR. TOOLE: The serum phosphorus corrected whether or not the patients received supplement in that group of patients.

DR. LUKERT: What would have happened in those patients that didn't receive?

DR. TOOLE: In the 51 patients who didn't receive phosphate supplementation, they also had at most two visits with the abnormality.

DR. LUKERT: Did you ask about bone pain?

DR. TOOLE: There were two reports of bone pain, and in each case, those were transient and related to recent traumatic event.

DR. LUKERT: Were questions specifically asked about long bone pain?

DR. TOOLE: There was no solicitation by the investigators for the incidence of bone pain, no. The investigators, however, were asked to inquire about any possible fracture which would be secondary to an emergency room visit, so we captured as much data as we could regarding bone fractures.

DR. GULICK: Other questions, Dr. Lukert?

DR. LUKERT: No. Thank you very much.

DR. GULICK: Thank you.

At this time, I would like to turn it over to Dr. Teitelbaum.

DR. TEITELBAUM: Thank you. Good afternoon, ladies and gentlemen.

With Dr. Bone's forgiveness, I just want to brief the panel about some definitions of bone biology and bone pathology, because I think it puts in perspective the lesion that we are purporting to be looking at.

When most of us think of systemic bone loss, we think in terms of the disease osteoporosis, and I just want to be sure that everybody understands that we are not dealing with osteoporosis here. Osteoporosis, by definition, is a decreased mass of normal and mineralized bone.

We most commonly see it following the menopause, and what happens in osteoporosis is that the bone resorptive cell, the osteoclast becomes overactive, if you will, it degrades bone at a much more rapid rate than it is being made, and it is being made at least the normal rate.

Now, in osteomalacia, what happens is bone is being made normally. Bone matrix, the organic matrix of bone is synthesized normally, but there is a defect in its mineralization. So, what happens is the unmineralized bone matrix accumulates. It accumulates because it cannot be mineralized in the setting in which it finds itself.

I will return to osteomalacia in a moment, but just parenthetically want to say that osteonecrosis, on the other hand, is a very different phenomenon. What osteonecrosis represents is actually death of bone, and the most common circumstance which you see it is in prolonged glucocorticoid therapy.

Now there is compelling evidence this is, in fact, due to enhanced apoptosis of bone-forming cells and osteocytes, but let's return, if we will, to osteomalacia.

As I am sure Dr. Bone and Dr. Lukert will agree, osteomalacia is a disease that bone doctors love to see, and it is the disease that bone doctors love to see because we can cure it, and we are much more effective in treating osteomalacia than we are in curing osteoporosis.

There are a variety of causes of osteomalacia, but clearly the most common one in our society is hypophosphatemia. Now, you will note that I did not say hyperphosphaturia. I am talking about hypophosphatemia, because at the end of the day, what really counts here is not how much phosphate is being excreted in the urine or being absorbed from the gastrointestinal tract, it is how much phosphate the bone sees.

If the circulating levels of phosphorus are normal, the patient will not develop osteomalacia. A question came up, Dr. Bone raised the question about the histology of the monkeys that received four times the dose of the drug, and it is a very good question, but I want to point out that those animals were not hypophosphatemic, and them not being hypophosphatemic really is prima facie evidence that they did not have osteomalacia.

If I can just stress once again, what we are really asking the question about is not hyperphosphaturia, but whether or not there is an impact on the circulating levels of phosphorus, and I think the data substantiate the fact that this impact is not substantial.

I have, in fact, looked at the bone of the monkeys with osteomalacia, and they did, in fact, have severe osteomalacia, but what was really striking about it, and which is a paradigm for the human disorder, is that it is completely reversible.

When the parallel monkeys came to necropsy, the osteomalacia was completely healed, and that is what we see in man, and there are two examples that I would like to discuss with you. One is the disease known as oncogenic osteomalacia, and an oncogenic osteomalacia is patients who specifically have mesenchymal tumors. They have severe enhanced excretion of phosphorus in the urine, they develop severe osteomalacia. You find the tumor, you excise it, and they completely normalize.

The other example is patients who have excessive antacid therapy. They are binding phosphorus in the gut, they can develop severe osteomalacia, we encounter them not infrequently. We take them off the antacids, we phosphate supplement them, and they completely normalize.

So, the point that I want to get across to you is we are not dealing here with an irreversible disorder should it exist, should it exist, and there is really no evidence that it does exist in these treated patients, but in the worst case scenario, this is not an irreversible disease.

Now, I want to close by just talking about what the possible worst case scenario is. Let's assume that we have a patient who, for some bizarre reason, takes the amount of this drug that Jib Gilead gave to the monkeys, and develops a severe osteomalacia that the monkeys developed.

Well, this would be detected, the patient would be taken off the drug, phosphate supplemented, and completely cured. But I want to close with that point, that we are not, in fact, dealing with an irreversible disorder.

Thank you very much.

DR. GULICK: Thank you, Dr. Teitelbaum.

I want to hold further discussion on these points until we get to the actual questions.

At this point, I want to turn to the open public part of the hearing. We have had four speakers who have signed up, and I would like to invite them to take the podium. The first person to have signed up is Dr. Yvette Delph, who is from the Treatment Action Group.

Dr. Delph, wherever you feel comfortable, back there or up here, as you like it.

DR. DELPH: Good afternoon, ladies and gentlemen. Thank you for allowing me to present the position paper on the accelerated approval of tenofovir DF.

My name is Yvette Delph, and I am the Antiviral Project Director for the Treatment Action Group, which is a community treatment activist organization. The copies of the TAG position paper are on the back table, and they have some extras for anyone who may need them. I think each of the members of the committee should have received one from me earlier today.

First of all, I would like to very highly commend the sponsor Gilead for conducting pivotal registrational trials of tenofovir DF in such highly treatment-experienced individuals. Tenofovir DF has a highly favorable resistance profile both in vitro and in vivo, and has demonstrated its efficacy against multinucleoside-resistant HIV.

Administered as one tablet, once a day, tenofovir DF makes a substantial contribution to the simplification of antiretroviral regimens. Since tenofovir inhibits HIV-1 reverse transcriptase at concentrations that are approximately 3,000-fold lower than that needed to inhibit DNA polymerases beta and gamma, it has very low potential for mitochondrial toxicity and, to date, there has been no evidence of mitochondrial toxicity due to tenofovir DF in clinical trials.

Tenofovir DF has a favorable side effect profile and both in Studies 902 and 907, the occurrence of clinical events and laboratory abnormalities in the 300 mg daily arm was similar to that in placebo.

There is no hepatic metabolism of tenofovir and it is excreted unchanged in the urine by the kidneys. Thus, there is potential for interaction with other drugs that are renally excreted and there is likely to be a need for dosage adjustment in individuals with renal impairment. Tenofovir is not a substrate, inhibitor, or inducer of the cytochrome p450 family of liver enzymes. It therefore has a low potential for drug-drug interactions involving this family of liver enzymes.

Tenofovir DF has been studied in very few persons with viral loads over 50,000 copies/mL. Therefore, there are not enough data to assess the efficacy of tenofovir DF in this population. Because of earlier concerns that we have heard about bone toxicity, tenofovir DF has not been studied in children to date.

The Treatment Action Group is in favor of accelerated approval for tenofovir DF for use in combination with other antiretrovirals in the treatment of adults with HIV infection.

The FDA should require the sponsor to complete the following studies in the postmarketing period:

A safety and efficacy study in individuals with viral loads over 50,000 copies.

A safety and efficacy study in treatment-naive individuals, and such a study (903) was fully enrolled in January 2001. In fact, looking at the demographics that were presented thus far for the patients who were enrolled at baseline, the median baseline viral load was, in fact, close to 100,000.

Safety and efficacy studies and pharmacokinetic studies in children.

Safety and pharmacokinetic studies in individuals with renal or hepatic impairment.

Studies to identify long-term toxicities of tenofovir DF, and in particular also, to follow more closely the potential for bone toxicity in individuals.

Drug-drug interaction studies with drugs that inhibit renal tubular secretion such as trimethoprim or cotrimoxazole which includes trimethoprim, and probenecid, drugs that are excreted by the kidneys and are likely to be used concomitantly by some HIV-infected individuals, such as stavudine, certain antibiotics including aminoglycosides, cephalosporins, and penicillins, narcotic analgesics, such as demerol and morphine, lithium and digoxin, and the studies which the sponsor has indicated that it plans to conduct with ddI EC, methadone, oral contraceptives, and adefovir.

We also need more data on the clinical correlation or we need data, because there are none, on the clinical correlation of the IC50 or IC90 with plasma levels of tenofovir.

There are several additional issues that TAG wishes to raise:

Gilead is the first sponsor to respond to the calls from the community to study investigational agents in highly treatment-experienced individuals and should be congratulated, not penalized, for this.

TAG is however concerned that a 48-week dose-finding study was conducted in individuals, virtually all of whom had HIV resistance to at least one class of antiretroviral agents and many who had resistance to more than one class. The FDA should require sponsors to determine the appropriate adult dose for antiretroviral agents before proceeding to large Phase III studies, especially in individuals with limited treatment options.

There is not yet enough evidence that tenofovir DF should be used only with nucleoside reverse transcriptase inhibitors. Until there is more evidence, tenofovir should be used in conjunction with at least one protease inhibitor or a non-nucleoside reverse transcriptase inhibitor and at least one nucleoside reverse transcriptase inhibit.

Some have questioned whether broad approval for tenofovir DF should be granted when the data submitted to date focus on experienced individuals. Here are several reasons why TAG would urge the FDA to grant accelerated approval for the use of tenofovir DF in combination with other antiretrovirals, in the treatment of adults with HIV infection.

Precedent. Since the 1995 approvals of lamivudine and saquinavir, the FDA has used this language for approving new antiretroviral agents even though pivotal studies were not done in certain important HIV-infected populations.

Although some thought that these broad indications would let industry off the hook for postmarketing studies, both Glaxo and Roche continued developing 3TC and saquinavir respectively, unlike that which Roche did with ddC after 1992. With the advent of HAART, these additional indications proved very useful.

Timing. Gilead did not have 24-week pivotal data on naive patients in May 2001 when it submitted the NDA. However, its pivotal study in treatment-naive individuals fully accrued in January of 2001, and so 24-week data is likely to be available within a few months, possibly early in 2002. Gilead could not, therefore, avoid doing the necessary study in naive individuals postmarketing. It has already been done.

Logic suggests that if the drug reduces HIV RNA by about 0.6 log, in treatment-experienced individuals, it will reduce viral load by even more in naive individuals.

Safety data are available in both populations in real time; to date there has been no serious safety problem in either population. In fact, tenofovir DF has a very favorable safety profile in the treatment-experienced, the population for which the safety data have been analyzed. In fact, the population for which toxicities are often even more of a problem than in the naive population.

Weight of Evidence. Cumulatively, the drug has good potency, a favorable resistance and safety profile. It is easy to take and generally well tolerated.

Finally, consistency. For years, the community has been asking industry to study new drugs in experienced patients, as well as in naive patients. Unlike Abbott, which is a giant pharmaceutical company with lots of resources, which could therefore submit an NDA for lopinavir/ritonavir containing pivotal data on naive and experienced patients, Gilead is a relatively small company with fewer resources.

We might wish Gilead had studied both populations in parallel, but they had just had a setback with adefovir and had been required to get 48-week safety data for tenofovir DF for renal and bone toxicity. We should not penalize them for going sequentially.

Also, I would like to note that the community is concerned that if a very limited indication for treatment-experienced individuals only is given, then, access by treatment-naive patients for off-label indications may be restricted.

We are concerned that HMOs, ADOX, Medicaids, and so on, may not be willing to provide drug for an off-label indication for naive patients. While we recognize that the situation may be favorable in states like New York and California, very different circumstances may apply in certain other states like Texas, Alabama, or Georgia.

I would also like to ask Gilead to analyze Studies 902 and 907 data, to look at outcome based on the number of classes of antiretrovirals to which subjects are resistant at baseline.

If anyone needs more information or wants a full statement electronically, it is available on the web site for the Treatment Action Group, which is www.treatmentactiongroup.org.

Thank you very much, Mr. Chairman.

DR. GULICK: Thanks, Dr. Delph.

The next speaker is Mr. Brett Grodeck, who is from Santa Monica, California.

MR. GRODECK: My name is Brett Grodeck. I am here not to give a rigorous scientific explanation of tenofovir. I am here to talk about what it is actually going to do in the community when it is approved.

[Slide.]

Just to give you some background, I am formerly editor of Positively Aware, formerly managing editor of HIVandHepatitis.com, and I work with the Rand Corporation in Santa Monica, California. I also have some background in pharmaceutical public relations. I bring this up for a reason I will get to in a moment.

[Slide.]

My purpose for speaking here is really to talk about a side effect of tenofovir, something I haven't read much about, haven't heard much discussion today, but I consider it an important aspect of the approval of tenofovir in real life.

I am asking the FDA to consider the long-term effects of tenofovir on the hepatitis B virus. Obviously, I would like to call for more long-term research, some short-term actions, and what I would like to do is try to give some contextual perspective to introducing tenofovir into the real world.

[Slide.]

I am sure some of you are asking why this is relevant to approving tenofovir for HIV infection, but in the real world, and in some cases up to 10 percent of HIV-positive people in the United States are also coinfected with the hepatitis B virus.

That number is probably high, but these are essentially the same people. They are in the same risk group, and they can jump from group to group.

Also, coinfection with HIV and hepatitis B ultimately results in greater liver damage. I have given the committee some background material. Again, I understand it is not the scientific rigor that you are probably accustomed to, but from somebody who, in fact, has HIV and chronic hepatitis B, and is taking tenofovir, it is kind of this real world situation that I would like you all to consider.

Obviously, we have all heard reports of liver damage rising in HIV population. Sometimes I have to ask what is the point of approving more drugs for HIV when we are seeing more and more liver damage. We are keeping people alive in order to see them die of cirrhosis, liver complications.

I am also here to represent a very undervalued group, and that is people with chronic hepatitis B. I understand that hepatitis B probably doesn't have the kind of media value that, say, hepatitis C or HIV has. It is an old disease, it has a vaccine to prevent it. It is probably most prevalent among drug users. So it doesn't make for good headlines, it doesn't make for good press.

But my question is - so many people with HIV are seeing liver complications. We are ultimately being forced to make a choice between dying of HIV or dying of liver disease. The way I see it, dead is pretty much dead however you get there.

[Slide.]

I am sure you are all familiar with lamivudine. Clearly, it was a blockbuster for its maker, Glaxo. Also, gets some recycled profits from that by clearing it for hepatitis B. I am sure a lot of you are familiar with entire process, but now, so many years after it has been approved, we are seeing what happens to lamivudine when it is introduced again into the real world.

Studies have shown that in HIV-positive people, hepatitis B virus, resistance develops in about half of people who take 3TC, lamivudine, and after four years, 90 percent of those people will develop resistance. That is hepatitis B resistance among HIV-positive people.

I have also read recently that the transmission of lamivudine-resistant hepatitis B virus is being transmitted into areas of the world where lamivudine has not been formerly introduced. What that means is you can probably transmit resistant virus.

So, so many years down the road, so many approvals later, what have we learned from treating HIV? Clearly, monotherapy for viruses don't work. We see it in hepatitis C, we are seeing it in hepatitis B, and I am sure in other areas. Multi-drug combinations are really the only way to fight a virus in the long term.

We also know from treating HIV and hepatitis B that drug companies can still make their profits before completed combinations are available to the public. We introduced AZT, we introduced ddC, ddI, d4T, and 3TC all before they were paired up to make a potent combination. We are doing the same thing with hepatitis B right now, and we are seeing the same thing, but no one seems to be bringing it to the front.

[Slide.]

I think it is important for you and everyone here to know about adefovir. Clearly, adefovir, clearly, Gilead has had a role in the HIV community. I think they have tried to participate. They have done some good things, they have done some things that the community may not have liked, but ultimately, adefovir for HIV was flawed, it didn't work, and I know that Gilead kind of feels burned by the HIV community. I think there is also sort of a subtle fear of adefovir among the community, among patients, which may be some of the reason why Gilead is trying to distinguish adefovir from tenofovir in terms of HIV and hepatitis B.

I think it is great that Gilead is pursuing adefovir, it is in Phase III. It is very promising, it is probably the most promising if you have chronic hepatitis B. That is really the only thing to look forward to if you have resistant lamivudine virus.

So far the data has reported there hasn't been any resistant hepatitis B virus, but as we all know, it is just a matter of time.

[Slide.]

I am not a scientist or a doctor, so I can't really take you through the intricacies of the science here. I have brought a couple of slides that have some things that anyone can look up on the web.

I will tell you my own personal experience. As I mentioned, I am HIV-positive. I have chronic hepatitis B. I did my own research and discovered that what was only available to me at the time was tenofovir. My HIV was completely under control, it hasn't been a problem for years. My hepatitis B was out of control, and I really had no recourse. I could not get into an adefovir study, and my liver enzymes were rising. I was between a rock and a hard place.

I researched it and discovered that tenofovir has significant activity against hepatitis B virus. Because I am HIV-positive, I qualified for the expanded access trial. I got tenofovir. I have been taking it for two months now. My hepatitis B viral load has gone from greater than 5 billion to 68 million.

Now, I can't tell you exactly what that means, and I can't tell you what that means in hepatitis B terms, but I can tell you that my liver enzymes dropped from 187 to 106 in two months, and that is just because of tenofovir. I think it is important to consider that this is going on.

This is just your standard data, and the next slide is, as well.

[Slide.]

I wish I could interpret this last bullet for you, but again I don't have a science background, but I get someone here could, and could probably tell that tenofovir and adefovir probably have about the same activity against hepatitis B, at least it did for me.

[Slide.]

I think if you are all here to consider what tenofovir will do in real life, I would like to ask the committee to consider that it will be a blockbuster, it will be huge, something like Sustiva, and everyone will be taking it, everyone who is HIV-positive, and anyone who has chronic hepatitis B.

What you are doing is you are introducing it into a population where up to 10 percent of those people have chronic hepatitis B. I tried asking Gilead. I couldn't really get a clear answer, and I understand that it is complicated, I do understand that.

But what I think is important for the committee to consider is will introducing tenofovir into an HIV-positive population ultimately lead to the emergence of resistance hepatitis B virus in that population, and if so, will that resistant hepatitis B confer to adefovir.

I have a gut feeling that that is worth looking at, and I want to look into why has Gilead sort of not talked about its anti-hepatitis B properties. I don't know, maybe they are recouping losses from adefovir, from not being approved. I can't say, but it's worth talking about.

Finally, by approving tenofovir for HIV, what are you saying to the hepatitis B community, who has chronic hepatitis B today, are you saying that HIV-positive people somehow get this drug because their disease is more political, more important, are sort of white gay men getting drugs faster than typically drug users who have chronic hepatitis B? I don't know, I don't know the answers to those questions, but I think they are worth considering.

I also understand that Gilead is a small company relatively, and I understand the whole position of the small but well intentioned company. Having work in pharmaceutical public relations, I know this line really well. I have written it into scripts and proposals, and it was sort of a standard phrase that I used, "small but well intentioned," both true and overstated.

I also know that in pharmaceutical public relations, I have cut checks to members of the HIV community, and I am sort of am proud of some accomplishments in terms of public relations having influenced the very committee that I am talking to today.

[Slide.]

Finally, I think tenofovir should be approved. You know, I didn't use it for HIV, I am using it for chronic hepatitis B. So, I hope it is approved, but I hope that the committee and I hope that the research communities, and I hope that Gilead defines tenofovir's role with hepatitis B, and they make that aware to the public easily accessible.

I think that the labeling for tenofovir should be strong, unlike the labeling in lamivudine. It's a side note, and, you know, side notes kill.

HIV doctors who are relatively narrow-minded into the HIV world tend to forget that there are other diseases out there, and they are prescribing 3TC to people who may be coinfected. They may not even know, and they are wasting the drug.

I think this is also a really great opportunity for Gilead to take the lead in coinfection causes. I don't think it's an expensive option. I don't think this is something that is impossible to do. I think it is an arm of the marketing department to educate doctors and thought leaders about the coinfection strategies and issues.

That is it. Thank you.

DR. GULICK: Thanks very much, Mr. Grodeck.

MR. GRODECK: If anyone has any questions, thanks.

DR. GULICK: Thanks.

Our next person to sign up is Ben Cheng from Project Inform in San Francisco. That doesn't look like Ben.

DR. DELPH: Mr. Chair, Ben Cheng would like to apologize, but he had a plane to go and catch, so he has asked me to read his statement instead.

DR. GULICK: Okay.

DR. DELPH: I will read it verbatim, so you may need to use your imagination here.

My name is Ben Cheng and I am the Director of Antiviral Advocacy at Project Inform, an HIV information and advocacy organization based in San Francisco. My organization and I have not received any funding from Gilead Sciences to be here today.

I am here today to support approval for tenofovir. The data that have been presented clearly demonstrates that the drug has convincing activity against HIV among antiretroviral-experienced patients, and what so far seems to be an exceptional level of short-term safety compared to most other HIV medications.

We are not concerned that the levels of viral load suppression and CD4 cell increase might appear meager when compared to some other classes of drugs since these data come exclusively from people with long prior histories of treatment use.

The results cannot fairly be compared to studies of other drugs in naive patient populations. Most important, these results suggest significant potency against most nucleoside-resistant virus.

There is large and growing need for new compounds that can work despite prior nucleoside resistance. Even though the current data come solely from a treatment-experienced population, Project Inform supports an indication for tenofovir that is not limited to antiretroviral-experienced patients.

We feel that tenofovir should be approved widely for the treatment of HIV disease, similar to the indication other HIV therapies. No HIV AIDS drug that worked in experienced patients has ever failed to work in treatment-naive patients. On the contrary, in almost every known instance, they have worked better in the naive population.

While drug safety can be a consideration when giving a new drug to a naive population, that does not seem to be a factor here given tenofovir's excellent safety record to date.

Most HIV therapies have been tested primarily in naive patients, yet, have been given indications for all stages of HIV disease. This drug has been tested first in the more difficult setting of experienced patients, and it should be, if anything, easier for foresee good activity in the naive population.

If tenofovir were only approved for experienced patients, then, there may also be problems in the future for some people in getting the drug reimbursed or problems accessing the drug.

Gilead Sciences should be applauded for taking the risk in conducting their studies among experienced patients instead of the normal drug development path of conducting studies in naive patients.

Many HIV community groups have long urged industry to conduct studies for antiretroviral-experienced patients. If tenofovir were to get approval only for antiretroviral-experienced patients, this could set a bad precedent that will likely result in industry returning to only conducting studies in naive patients. As a result, people with limited treatment options are the ones most likely to be hurt by this. End of quote.

Thank you, Mr. Chairman.

DR. GULICK: Thank you, Mr. Cheng.

Our last speaker to sign up for the open public hearing is Jules Levin from NATAP in New York.

MR. LEVIN: Hi, everybody. Many of you know who I am, Jules Levin, the founder and executive director of the National AIDS Treatment Advocacy Project based in New York City, NATAP for short. I am very proud of the work that NATAP does and the work that I do.

I have had HIV and hepatitis C for 18 years, and the primary mission of NATAP is to provide treatment education and information to people all over the world. That is what we do, for people who don't know what we do.

In particular, we provide a very wide and deep treatment education program for people in New York City, for people with HIV and for case managers and medical professionals. As a result, I come in contact and my organization comes in contact with thousands of people with HIV, literally, frankly, every day, and that is not an exaggeration.

So, I come here to speak to you for myself and I think for some of the concerns of people with HIV and hepatitis. So, I am going to be brief, I don't have a lot of explanations, I am going to raise a few points.

If you look at the safety and lab data with regards to PMPA, tenofovir, ALT elevations don't seem to occur, it is kidney excreted, if not completely through the kidney, at least mostly through the kidney.

I think when we are talking about a Phase IV study, we need to explore the use of tenofovir in people coinfected with HIV and hepatitis C, both people who are naive to HIV treatment and people who are experienced, and we need a study that looks at biopsies to really see if there is a difference, not just in ALT elevations, but also in the liver itself.

Without doing a biopsy in such a study, the results will always be questioned, and I strongly recommend that that be required for a Phase IV study.

I think that this drug in a treatment-experienced population, this is a very important drug and people are waiting, and have been waiting, for this drug and other drugs like this who have resistance and are failing therapy, and have lots of treatment experience.

I think the resistance profile is very impressive, and I think that our population, this drug really needs to be approved pronto and in the pharmacy right away.

I feel that my hand is forced to state my position today. I have some concerns about a first-line indication. To date, I know that there is a study going on in treatment-naive, it is unblinded. It is blinded at this point, and we don't have the data, and maybe we will have the data in a couple of months, and it probably will look good, but we don't have the data today.

The study looks at PMPA as a substitute for a nucleoside, so it efavirenz/3TC and d4T, or efavirenz/3TC and PMPA. Well, with a first-line indication, what about the doctor that wants to use PMPA, abacavir, and another nucleoside? We need a study. That is a Phase IV study that needs to be done.

Another point that I have a concern about, which we seem to be very unclear about today, and I would like Gilead and the panel, some very esteemed HIV doctors and researchers here on the panel to discuss this point, so that we could come away with a more clear indication about this.

That is with regards to the 184 mutation. Does the 184 mutation really improve the response to PMPA, and does 3TC therapy have to be continued to do that? If you look at the briefing statement, I am glad the FDA--the FDA deserves a couple of compliments here, too--the FDA put the briefing statement, I think for the first time, on their web site, and I am pleased about that, so I read that because I didn't get a book, because I am not on the panel, and I think that the data on this question is unclear.

At the fourth resistance workshop, Gilead presented some convincing data that the 184 increased the response, and the question is was 3TC still present to maintain the 184. That question is uncertain. Maybe Gilead can answer this question, because there is a lot of data in the book, and it was discussed here about if the 184 is present, maybe it does improve response, but it didn't talk about how many patients were maintained on 3TC, and maybe the 184 was there with 3TC present or maybe without 3TC present. I don't know the answer to that, but there is a couple of resistance experts on this that I know that can direct this question.

One other point I would like to raise. I think that the point that was raised by Brett, I think can be addressed in labeling, and I would like the panel and Gilead to discuss this, addressing this in the label, at least consideration of this question of addressing it in the label. Maybe we can have some discussion about this here this afternoon.

One concern I do have, and maybe Gilead and the panel can address this, is PEG-Intron, the Schering pegylated interferon is excreted by the kidney, and so is PMPA. So, the concern I have is, is that people who have HIV drug resistance, who have HVC, maybe on PMPA, maybe also starting to take peg enteron. So, I would like to have some discussion about that.

I also have no concern as some of the other community people spoke about the CD4 increase. I don't think that that is an issue.

So, in the end, I think I have raised my points that I think need to be address, and I just want to say that I do strongly support, and I think that the community, people with HIV, really need this drug for treatment-experienced people right away.

Thank you.

DR. GULICK: Thanks, Mr. Levin.

If there are no other people who wish to speak at the open public part of this meeting--seeing none, we will go ahead and close the open public part.

I would like to turn now to Dr. Kim Struble from the FDA, who will present the charge to the committee.

DR. STRUBLE: I am just going to go through the questions and provide some background information to help with the deliberations this afternoon.

[Slide.]

For the first question, we would like discussions on in what patient population has tenofovir demonstrated efficacy and safety, and for what indications should tenofovir be recommended.

Should it be recommended for the treatment of HIV infection, which includes both naive and treatment-experienced patients, or should it be recommended for the treatment of HIV infection in patients who have received prior antiretroviral therapy.

[Slide.]

The second question deals with the bone abnormalities. We would like to hear your assessment today in the preclinical and clinical data with regard to bone effects. We also would like to hear if there are additional nonclinical or clinical studies that Gilead should conduct to further evaluate tenofovir-associated bone effects.

[Slide.]

This slide here has a brief summary of the nonclinical studies that are completed and are ongoing. They have completed a 42-week rat and dog study, several monkey studies ranging from 14 days to over two years in dosing, reproductive/toxicology studies, and some mechanism studies.

There is two ongoing, a two-year rat and mouse carcinogenicity studies, to also assess bone affects.

[Slide.]

With regard to the clinical data, Study 903 will provide comparative data in 601 patients for approximately 96 weeks in duration.

Bone mineral density and bone biomarkers will be available for all patients.

Also, in Study 910, which is a rollover study from Studies 901, 902, and 907, this study will provide follow up on approximately 575 patients for four years, and the bone mineral density substudies will continue over this time period. In both Studies 903 and 910, fractures will be evaluated.

[Slide.]

Regarding clinical resistance, we would like comments today on the resistance analyses that were presented by the FDA and by Gilead this morning. We would also like your recommendations for the type of clinical virology analysis that should be conducted for future antiretroviral drug development and suggestions for the type of resistance data/analyses warranting display in package inserts.

One of the issues regarding Phase IV commitments that we would like to bring up is drug interactions, because tenofovir is renally eliminated. Gilead had made a statement this morning that there were no clinically significant drug interactions, but we feel that we probably cannot definitively say that because potential interactions with other drugs that are renally eliminated have not been evaluated yet.

An interaction was seen with ddI, which is the buffered formulation, not the enteric-coated formulation, in which there was AUC increases of 44 percent and a Cmax increase of 28 percent. No dose adjustments are being recommended, and we feel that patients should be monitored for ddI-associated adverse events if they are taking the two drugs concomitantly.

[Slide.]

So, finally, we would like your comments on the proposed second study for traditional approval, and would also like to hear comments for other study designs or patient populations that should be studied as Phase IV commitments.

Thank you.

DR. GULICK: Thanks, Dr. Struble.

DR. GULICK: Could we go back to Question No. 1. I think we want to handle each question separately. I would like to give people, everyone on the committee, an opportunity to respond to the different parts of the questions.

For Question No. 1, I think I would like to conclude our discussion actually by going around the table and having people state how they feel about the indication, but let's take the questions first and try to generate some discussion on the very first question.

In what patient population has tenofovir demonstrated efficacy and safety? Who would like to start? Dr. Wong, thank you.

DR. WONG: I haven't talked yet today. As I read these data, the drug has been shown to be efficacious in naive patients in a short-term study and in experienced patients in both 24 and 48 week follow up, so I think it has been shown to be effective, and effective in both those populations and safe so far in both those populations.

So, the corollary is that I would recommend approval for both groups.

DR. GULICK: Dr. Yogev.

DR. YOGEV: I would put a little bit of number on this statement. I don't think it was proved to be effective, at least to my satisfaction, patient with a high viral load, who were experienced. I did a minor calculation by the data which was supplied to us.

Supposedly, 155 patient total had less than 400, which is 45 percent of the total population. We had only 15 percent out of 99 patients who had more than 5,000 or less than 400. The whole effect of this drug of being average 0.6 of viral load decrease, I would urge to think a little bit more carefully - is it really effective for patients with a high viral load.

With naive patient, I think the number are too small to make any decision, and I would like to suggest that at least I didn't see enough data for efficacy in naive. There is no question in my mind that it will show efficacy, the question will be hopefully later do we want to put it as the first choice, keeping in mind how well it might be working in the population which was tested.

DR. GULICK: Dr. Hamilton and then Dr. Pomerantz.

DR. HAMILTON: Without disagreeing with the former two speakers, I would like to add a qualification to the qualification. Whether or not naive patients have been shown to respond favorably, I think is of less concern to me at the moment, because I suspect that they will given the fact that treatment-experienced patients have, but of greater concern to me are two points.

One is that I share Dr. Yogev's view that we have not demonstrated conclusively that patients with higher viral loads, more advanced disease, equally treatment-experienced, have been shown responsive. I believe with that caveat, that I personally would favor at the very least some serious attempts on the sponsor's part to address that question.

Of equal concern to me, however, and some of you will recognize instantly where this is coming from, is that the target population that has been principally addressed here are patients in whom I might not consider a treatment at all, given the development over the past number of years of a revised opinion about when criteria are appropriate to change or add drugs in the course of long-term management.

If a viral load is in the 4 to 10 to 15, even up to 20,000, and the CD4 is as high as it is here, very honestly, it is not an automatic for me to want to, and certainly I don't feel compelled to add something in a futile attempt, in my view, to drive the viral load to undetectable, which I think is (a) impossible in many cases, impractical in even more cases, and possibly unnecessary in all cases.

So, with those overall comments, I guess I have given my preliminary opinion here.

DR. GULICK: Dr. Pomerantz and then Dr. Schapiro.

DR. POMERANTZ: I think this is a bit of a tough call because there is some data that is missing, and yet, most people hand-waving would suggest that they know what that data will probably turn out to be empirically.

Two issues. I think the one thing that is clear is that there isn't enough data above 50,000 in high viral loads. I think it becomes even more important when you add high viral loads in naive patients, because you don't have data there for either, and the group that I would be more concerned about are high viral loads in naive, because you have two lacking data sets there.

The second thing is that this is a different time period. There are a number of drugs in the armamentarium for naive patients, but not for many people who are in salvage therapy than the first or second, and that is where I think that modest to low viral loads, and sometimes when you have nothing else, tenofovir would be, and will be, a great drug when I would assume it will be approved. I think that has been shown reasonably well.

I think that for naive patients, there is enough there to make them show us one more time that this actually is going to work. It is not five years ago. There are a number of drugs you can take upfront that are low pill burden, and I don't think that you need to jump the gun in those patients. I think it was nicely said by a variety of people, including our patient advocates, that it is the salvage patients that really will be able to use this, and should be there relatively quickly.

So, I would recommend its use for those who have had prior experience. I would not yet recommend its use for those who are naive, and certainly those who are naive with a high viral load.

DR. GULICK: Dr. Schapiro and then Dr. Tebas.

DR. SCHAPIRO: I would continue the thoughts of Dr. Pomerantz. I think that the question really is the risk-benefit ratio. I think, looking at the two groups, it is not if it is naive or experienced. I think in patients who do not have other options, even though there are concerns that we have not seen all the data we want to see, we haven't seen drug interactions, which I think are important, which were brought up here and have not yet been addressed.

I think we have concern about some of the protease inhibitors, some of the dose of the protease inhibitors. We don't know what that will do. I think some of the populations that we really want to treat were not studied.

I think some of the populations, such as black women, we really don't know what the PK is happening over there. I think these concerns are risk. I think we have seen a benefit.

I think for patients who do not have many other options, the benefits do outweigh the risks, and therefore, I would strongly think that we should get this into the hands of those physician and patients right away.

The question is for patients who have many other options. Good studies are being done now, looking at if this drug is as good as others. Until we know if it is as good as the others, until we know how it does in interactions, until we know how it does in these different populations, I think the risk is greater than the benefit in patients who have many other options.

So, as opposed to, is the question naive, it is not specifically that it doesn't have efficacy in naive, I think it will have, but I think that because there is a lot of data that is still lacking, I think if we receive that data, we would be very happy to allow it in naive patients.

I think for now the risk-benefit works out to be still somewhat worrisome, and even I think again, just a word on the community representative who got up, I think those are all excellent points, and I also think that we don't want to penalize, of course, Gilead, for doing a wonderful job and being very brave, but if we start giving to naive patients, and find out that some of these risks really end being dangerous, it will be hard to take it back.

So, I think it should be in that context.

DR. GULICK: Dr. Tebas.

DR. TEBAS: I want to concur with Jonathan Schapiro. I have lived in this country for eight years, I live in a state that the motive of the state is Show me your State, and before using this drug in naive people, I want them to show that it is as good as other combinations that we have.

I think this period of the accelerated approval is to provide drugs where there is no options, and approving it directly for naive people, it doesn't meet those conditions, and I would wait.

Ideally, I will have the results of 903 relatively soon, and I assume as we see the data, I think it would be reasonable to approve for all HIV-infected people, even naive people, but before that, we run the risk of approving a drug that later on shows that it is inferior to current other label regimens, and we might be in a situation that it will be very awkward.

DR. GULICK: Dr. Munk.

DR. MUNK: Mr. Chairman, can I ask a question of FDA staff?

DR. GULICK: Sure.

DR. MUNK: Can FDA staff shed any light on the comment in Mr. Cheng's comments, that, in fact, prior anti-HIV agents had received the indication for which Gilead has asked based on data, for example, that may only have been generated in naive populations?

DR. STRUBLE: Yes, that is true. With the exception of Kaletra, the majority of the past approvals have been--

DR. GULICK: Can you speak up a little bit?

DR. STRUBLE: With the exception of Kaletra, the other drug development programs have been largely conducted in naive populations or patients with limited nucleoside experience. Kaletra was the first application to come forward with PI-experienced patients, that were experienced within its respective drug class. So, yes, all the other products have gotten a broad indication for the treatment of HIV infection, and that includes presumably all the spectrum of the HIV disease.

DR. MUNK: That being the case, and based on my reading of community comments, I think it sounds like it would be a departure from past practice, and, in fact, sensitive to the comments about potential risk of applying the drug to classes in which there is not yet demonstrated efficacy, it seems like we may be going in the wrong direction, that, in this case, the extension would be to naive patients, and I believe it is reasonable to assume that the risk would be less than with the case of these other drugs, where the broad indication would allow their use in experienced patients in the absence of such data.

So, I would, based on that, I would support the broader indication with the caveat that I am not comfortable with patients with high viral loads at this point, and that that perhaps ought to be a limitation on the indication.

DR. GULICK: Dr. Kumar.

DR. KUMAR: In everything that I have reviewed both from the material given to me, as well as everything that I have heard today, as a clinician, it is clear to me that in experienced patients, that tenofovir has a very potent use.

But I also want to make a very deliberate educated leap of faith and say that there was no significant safety concerns in this treatment-experienced patients that we are most likely to see the side effects.

So, I would feel very comfortable using it for naive patients while awaiting Gilead's full presentation of its data.

I think, as a clinician, that works in the trenches, and especially in states that look at ADAP programs that will only approve for indicated approvals, to allow such a good drug to come forward and not be allowed to use in all subsets of patients will be problematic.

DR. GULICK: Dr. Stanley.

DR. STANLEY: Well, I don't necessarily agree on that one. I think I can speak for the Texas ADAP program, since it is under my purview, and once a drug is approved and is either added to the formulary or not, we don't second guess how the physicians approve it.

I mean I have got 10,000 patients on that formula, on ADAP, and there is no way I am going to look at each and every one of those and try to second guess the physician. So, at least in Texas and, Yvette, I don't know where you got your reference earlier, but us making a limited approval would not affect its role or its availability in the ADAP program in Texas.

That being said, I continue to have concerns about making this broadly recommended, and that is, we really don't know what the best use of it is, should it be in a PI-containing regimen or does it not have to be, and that question isn't even planned to be addressed from what I can see, and I think that that is a study that I would like to see that question asked.

The proposed study is only going to look at it with an NRTI and an NNRTI. We don't know what the best way to use it upfront is, what the best combination is, and so it is clearly efficacious in salvage therapy, and I think that we should go with that. I think it is desperate that it is available for those patients that have been on multiple drugs, but I am very nervous with now making a broad recommendation on these data.

DR. GULICK: Dr. Wood.

DR. WOOD: Just to echo some of the concerns raised by Dr. Schapiro and others, clearly, there is a need for a new antiretroviral agent that demonstrates some efficacy in treatment-experienced patients, and as Dr. Schapiro elegantly highlighted, that based on the preliminary data we have seen here, there is a greater appearance of benefit compared to risk in treatment-experienced patients. For those who are naive, the risks would appear to be greater than the benefits.

The point that I would like to raise is, if the drug is approved, it is going to be used. The FDA, state agencies are not going to regulate how practitioners and those individuals in the trenches use this drug.

Based on Dr. Hamilton's comment of the current revision in the PHS guidelines, in which much higher levels of viral loads are tolerated before consolidation or intensification or even change in treatment therapy is recommended, the people who truly need a salvage regimen out there in the community are probably individuals with very low CD4 cell counts and viral loads greater than 50,000.

It is in that very population which is going to be rushing to seek the use of a new antiretroviral agent that we have the most limited data in.

So, I would like to again just reiterate that the sooner we can get information about the efficacy of this drug, not only in naive patients, but particularly in those individuals with viral loads of 50,000, because I think those are going to be the individuals that are clamoring for it and those are going to be the individuals, the prescribers, if the drug is licensed, are going to be prescribing it for.

DR. GULICK: Dr. Pomerantz.

DR. POMERANTZ: I just want to give a quick postscript, because I understood what Dr. Munk and my good friend, Dr. Kumar, said, and that is what I said at the beginning of my comment, which agreed with Dr. Schapiro, that it is a tough call.

But it is important to realize that this is a dynamic field, and being here for the last four or five years, we have seen how as the armamentarium changes, your ability to make different calls change as well.

So, with naive therapy, there is enough out there for most patients to give low pill burden, most patients, low pill burden, fairly easy drug input, and it is not five years ago. I don't think we need to have two data sets missing and place it where it is not absolutely necessary right now.

I would contend that in the trenches, as was said right now by Dr. Wood, where it is absolutely necessary or in the salvage cases, and the rest, we will see when the data is there.

DR. GULICK: Dr. Wong.

DR. WONG: I guess most people disagree with me, but I just want to put another face on what we are talking about. I don't think that we, on this committee, or the FDA, should really ask sponsors when they are requesting approvals to demonstrate that the drugs that they are requesting approvals for are the best available in all situations. I think that is not a realistic bar.

It seems to me that what is being proposed here is that Gilead be given an approval that is substantially more restrictive than the approval for really any other antiretroviral drug. I look at that in the context of their having shown us today very convincing data that their drug is efficacious in a group for which we haven't really seen these sorts of convincing data for efficacy before.

So, I really think that what they have shown is that their drug is safe and effective for adults with HIV infection, and I would not try to split that group to a greater extent than what we have done in the past.

DR. GULICK: Other comments? Dr. Englund.

DR. ENGLUND: I am concerned about licensing a drug or granting our approval to a drug for which there really isn't data, and my question is how long will it take as a new member here, a new potential member, whatever I am, how long will it take to move forward when they do get the data, because it seems to me that it is within the purview of this committee to recommend that when the data is available, that we should be able to move quickly and responsively to it.

I mean that is one of the concerns, is how long is it going to take.

DR. GULICK: Would you like to address that, someone from the Division?

DR. STRUBLE: How long it will take for?

DR. GULICK: The question is there is a naive study in progress right now. Let's say the committee recommends that it be only approved for treatment-experienced, but then this naive study becomes available, how long before that could be reconsidered in terms of the labeling of the drug.

DR. STRUBLE: Well, I think it depends on when the study actually gets submitted to us. When the study gets submitted to us, we will decide if it's a six- or 10-month review, and then we will take an action within that time frame, but I think it all depends when the data is going to be available and submitted to us.

DR. ENGLUND: I feel strongly that we do need this as a salvage protocol and that the data they submitted is good enough to consider this absolutely for the second group, for the patients who have received prior antiretroviral therapy.

DR. GULICK: Other comments? Dr. Johnson.

DR. JOHNSON: I agree with everyone, so I will probably not get asked back.

[Laughter.]

DR. JOHNSON: I think back to five years ago, and, you know, there weren't as many options, and 3TC was approved for naive and experienced patients, and we only saw half-log reduction, and we didn't care what their viral load was, and it still did better.

Here, obviously, we have all agreed that the treatment-experienced group, there was excellent data, trying to say that because they didn't study hard in 100,000 or 50,000, I think we are splitting hairs if we start restricting for a group that is desperate for a salvage drug, and I think there should be no upper limit on that, and they can gather more data, and we are all, in practice, giving four drugs anyhow often off-label, and I won't get invited back for that either.

But with regard to the treatment-naive population, let me again ask Dr. Struble, there is no precedent for half a labeling, right, we have no other HIV drugs that got approved and then we tried to go back to our universities and say remember you can't give that to drug-naive patients. It will happen, and I believe that I agree with Dr. Wong that I have probably seen enough to accept that I could give this to a treatment-naive person with an adequate risk-benefit ratio, with a low pill burden, with more safety monitoring, and would be happy to reconsider if something desperately jumped out, but I am not hearing that it will.

DR. GULICK: Dr. Sun and then Dr. Hamilton.

DR. SUN: I don't get to vote, so I don't have to take a position, but I would offer a few observations. I think, first, on the safety side, it seems like the evidence suggests that this is a fairly safe drug, and I think even though it was studied primarily in experienced patients, one can fairly easily make that extrapolation that it will have a similar profile in naive patients.

On the other hand, as someone pointed out, naive patients may have a different risk-benefit equation that they apply to a drug.

With regards to efficacy, again echoing many of the comments that were made, it is a lot easier to extrapolate going from experienced to naive than going the other way. So, I think there is biological plausibility for expecting that this drug will work in naive patients.

Although naive patients will probably tend to have higher viral loads than the patients that were studied in 902 and 907, we have to remember they will also be getting more active drugs than what they received in the trials that were conducted.

The third point is I would just caution people against making too many historical comparisons, because the field has changed so much. A few years ago we didn't have treatment-experienced patients or we didn't have PI-experienced patients when the first PIs came along obviously, so I think it is a little hard to compare today with three or four years ago even.

The last thing I would point out is that I think this becomes a little bit philosophical in terms of how much direct evidence you need to support an indication, and I would point out that we already do a fair amount of extrapolating, so I think most of the labels read that drug X is approved to be used in combination with other antiretrovirals without specifying what they are, and it is generally the case that clinical trials don't test every single combination that is available.

DR. GULICK: Dr. Hamilton.

DR. HAMILTON: Over the period of the four years that I have been on this committee, I have learned a number of things. One of them is that there are at least two potentially competing responsibilities that, as a member of the committee, I have perceived that I have.

I say potentially competing because they may be actually complementary, but the first, which I thought initially was my responsibility, was to evaluate the data and just be hard and fast, cut and dried, black and white, and while I think that is still an exceedingly important role, a second perceived responsibility, and one that I would say this is only by implication, not that anybody has ever told me this, but what we ultimately recommend as a committee, what we decide as a committee comes across to the public as a recommendation.

So, if we approve this drug, then, we in essence are recommending that everybody use it for whatever they want, and, in fact, they may do that, I don't know, they probably will, but I think it is important to separate in our own minds what it is that we are actually saying here.

I betcha we all pretty much agree very closely on what the data show here, but it seems to me ultimately, we are going to have to go beyond that and hopefully try and make some accommodation with a very cooperative sponsor in my view for satisfying these other concerns in a collegial and reasonable way without becoming too overly consumed with details.

Those are all just kind of very general comments. I don't know that they have any meaning for anybody for me, but I offer them.

DR. GULICK: Thanks.

Dr. Yogev.

DR. YOGEV: Well, it makes some sense to me, if it helps you.

[Laughter.]

DR. YOGEV: Maybe I didn't put it the first time. I am concerned about the data and the viral load also connected to the resistance that we didn't really put together, but if the viral load average median in those studies, 907, if I recall correctly, was 2,600, and 3 percent are resistant to the drug, on a virus which mutates so much and you are going to give it to the naive patient with a 50 and 100,000, are we going to see much more resistance developing.

Keep in mind that you are also exposing a population again to a single drug that 10 percent or higher are HBV, that are not yet suffering from it, but you are helping them to become resistant before you see what the benefit is, and there are so many other drugs around.

That is why I would like to see it, at this point, restricted to the smaller viral load, when it is active, or to the experienced patient, because they are really running out of choices. But I think the resistant issue over here, the way it develops, and way it was presented, is not clear to me there was a higher load and you won't see more.

DR. STANLEY: Dr. Hamilton, your comments did ring with me and meant a lot to me, and particularly the second role that you postulated for us, where we make a recommendation, and the public hears it, and that is what concerns me in this situation again is that this is a very important drug for salvage.

It is a very important drug for that population. Once it is approved and out there, yes, the people in the trenches will use it as they wish, and so it is not like we are truly limiting the drug, but yet what I am comfortable with, with what the science is that we have seen, is to say this is the area where we know it is efficacious is in this population, and that is where we target it.

What the individual prescriber wants to do is always up to them.

DR. GULICK: Let me try to summarize what we have been saying. In terms of what patient population, we are comfortable with safety and efficacy being demonstrated. The committee was unanimous in saying for the treatment-experienced population, that we feel quite comfortable that that has been demonstrated.

For the naive population, it was noted that there is relatively little data to go on. Several people voiced the probability that we can extrapolate from the experienced population in terms of virologic effect and safety issues to the naive population.

There was some concern about those with high baseline viral load levels, and it was noted that there is relatively little data to tell us about safety and efficacy in that particular group.

In terms of the indication, and again I will remind people after this I want to go around and ask each person what they would suggest, we had a lot of debate, and there are differences of opinions around the table.

Dr. Pomerantz summed it up best by saying this is a tough call, and most of this revolves around how much extrapolation you are willing to do from the data in hand. To support the concerns of the people who would seek to have an indication limited to treatment-experienced population, this thought primarily centered on several points.

One was how comfortable are we that there is no data to support this indication and how willing we are to extrapolate.

Number two, people made the point that this is a different time period in the evolution of HIV drugs. There are 15 drugs approved for the treatment of disease today.

Of note, one point that wasn't made was that in the accelerated approval guidelines is the quote that "a meaningful benefit over existing treatment must be demonstrated," and there was some discussion that we really don't have comparative data between tenofovir and the other agents that one might substitute tenofovir for in naive patients.

Dr. Schapiro brought up what is the risk-benefit ratio, and others echoed this and really said that the risk-benefit ratio in experienced patients may be quite different from those in naive patients.

People spoke about the safety issues, about drug interactions, about what are the optimal treatment regimens that you would use in each of these populations, what is the best combination of drugs.

These are questions that we simply have answers for. On the other hand, people who would support a broad indication, and several members of the committee support that point of view, really were more comfortable extrapolating data from what we know about the treatment-experienced group. People said we assume that it is okay from a safety and virologic point of view, it makes biologic plausibility that that approach would work.

There is precedence in labeling from past drugs to look at the other direction, going from naive to experienced, and doesn't it make some sense to go from experienced to naive.

People brought up concerns about the implications for access and reimbursement issues although others noted that there is precedence for off-label use in this field.

So, those are sort of the issues we considered as a committee. Again, I would like to go around the table and have people address what indication they feel is appropriate given everything we have said today.

I would like to start with Dr. Englund.

DR. ENGLUND: I would say for the second, for the latter, for the treatment of HIV in experienced patients.

DR. DeGRUTTOLA: Comments or just--

DR. GULICK: However you want. Certainly comments are welcome.

DR. DeGRUTTOLA: I would say that what the label should be depends on what we would really want to feel has been demonstrated for the drug. If the only requirement to have a recommendation for treatment of HIV infection were that tenofovir have activity in naive patients, my sense from listening to most people was that the belief was that it would have activity.

But if the reason for recommending the broader indication was the belief that a treatment that contained tenofovir was very likely to be non-inferior to some other standard regimens that are used, in other words, we could infer that the tenofovir-containing regimen would be at least non-inferior, there didn't seem to be a lot of support or evidence for people being willing to make that kind of claim, and unless there were someone who believed that they could defend that point of view, I would tend to recommend the second, narrower indication, but would be interested as we go around if there is anyone who believes such a statement could be supported.

So, my vote at this point would be for the treatment of HIV infection in patients who had received prior therapy.

DR. GULICK: Let me just say we are not actually taking a vote, but just so people know. This isn't a formal vote, but I would like to hear everyone's opinion around the table.

DR. WONG: I guess I would just reiterate that I would not recommend making a more restrictive indication in this case than we ever have before, especially since the sponsor has really done precisely what the HIV community and also this committee has asked before, and that is to specifically target treatment-experienced patients.

It is biologically implausible to me that an agent that has shown this degree of antiviral effect in patients who are heavily pretreated would not have at least that much effect in patients who have not been pretreated, and therefore, I think they should receive the same sort of approval that every other HIV drug has.

DR. GULICK: Dr. Schapiro.

DR. SCHAPIRO: I would just like to repeat one issue. It is not only the efficacy and the safety. I think part of the safety, drug interactions are important, and I do think that regardless of the other large studies being done, it would be relevant to see how it interacts with a drug that is going to be given with.

That is a big part of the risk-benefit ratio. We have had some discussions here at these meetings. I think Gilead has done a wonderful job, but I do think it is to be expected before allow widespread use to see the interactions, and I think some key interactions were not studied, and that is part of the risk, as well.

It is not only are we confident it will work, and I don't think that is too high a bar to ask of companies. I also think we should know if there is a PK difference in black women. I don't think that is something which is too much.

I think that those are some of the studies we should also see, and I think pending the results of this study, the large study that is ongoing, and some small PK studies, until we see that data, then, I would say for now it is to be in treatment-experienced.

DR. GULICK: Dr. Kumar.

DR. KUMAR: I agree 100 percent with what Dr. Wong just articulated, that given everything that was presented today, that it should not be a restricted indication, but be approved for just the treatment of HIV infection.

DR. GULICK: Dr. Hamilton.

DR. HAMILTON: I agree that it should be given the broad approval with specific information in the labeling that indicates where solid data exists and where extrapolation has been allowed, and hold Gilead's feet to the fire to deliver on the remainder of the data that we need.

DR. GULICK: Dr. Yogev.

DR. YOGEV: I just carry one step further your second comment before that we owe also the public any relation to something which we did in the past. Somehow my colleague failed to remember that many times it did fail in the experienced patient just because we did not indicate that we want to see data. To me, to go the other direction with the viral load, with the resistance, with the interaction, I feel uncomfortable, and I think we should reserve it to the population who really needs it before we see too much resistance.

Therefore, I would suggest only for the experienced patients.

DR. GULICK: Dr. Stanley.

DR. STANLEY: I, too, support only the narrow approval for the experienced patients. This is a whole new drug, and we don't yet know what combinations it is going to be best in, but we do know it is good in the treatment-experienced patients that need another drug.

So, it is not a PI so you can use it like the other PIs, you know, we haven't learned, we haven't seen what those combinations are yet. The other thing is that to me it really is irrelevant what we did in the past, what we did five years ago.

This isn't five years ago, it is today, and we have more knowledge, we have more tools, let's target this drug for now where it needs to go, and as soon as we have got data that shows its use as first-line therapy, I am happy to come back and approve that.

DR. GULICK: Dr. Bone.

DR. BONE: Well, it would presumptuous of me to have an opinion about this. It sounds like there are some issues about how the regulatory criteria for accelerated approval may have been applied in the past as compared to the criteria for traditional approval, and so on, but it just sounds to me like it is beyond my scope to answer this question.

DR. GULICK: We will count that as an abstention then.

Dr. Wood.

DR. WOOD: I think the points raised by Dr. Wong and Dr. Kumar are valid in terms of the expectation that it is not unreasonable to expect that treatment-naive patients would respond to this drug, given the efficacy that has been demonstrated in treatment-experienced patients, that naive patients would respond.

However, the fact of the matter is, is that we know that treatment-naive patients have high viral loads. That is a fact. The other fact is that we do not have efficacy data in terms of the response of individuals with high viral loads to this drug.

For that reason, I do not believe that it is reasonable to extrapolate back to naive patients that they will respond to the drug, because we have no idea in terms of how efficacious this drug is in individuals with higher viral loads.

So, I would recommend approval that is restricted labeling.

DR. GULICK: Dr. Pomerantz.

DR. POMERANTZ: It remains a tough call, but, Dr. Wong, I think that we are missing two data sets, as I have said before, that I think Dr. Wood is right, they are going to have higher viral loads now in naive patients in most cohorts. If you posit that this isn't going to work at very high viral loads, which we haven't shown whether it is or isn't in even the experienced, then, you are adding a potential problem where one is not needed to be added in 2001, and for those two reasons, I vote for a more restrictive labeling.

DR. GULICK: Dr. Dorsky.

DR. DORSKY: I support the broader indication.

DR. GULICK: Dr. Johnson.

DR. JOHNSON: I have heard everything that everybody said, and I think two things. One, I believe that it should get the broad indication. I think, though, I am basically conservative, and it should be restricted until we get the more complete data sets. We are in the year 2001. I think we need the data.

Can I just ask one more time, what is the earliest that we could get the data set? Kim?

DR. STRUBLE: Gilead can answer that.

DR. JOHNSON: Gilead? I am asking Gilead, if this is like it is available in two months?

DR. TOOLE: The last patient enrolled in Study 903 will complete a 48-week visit in December of this year. We are hoping to have something to submit to the Agency late the first half of next year, sometime in the May-June time frame.

DR. JOHNSON: So, Trip?

DR. GULICK: Which way are you going, Dr. J?

[Laughter.]

DR. JOHNSON: I am going to go for the broad indication because of biologic plausibility, the resistance profile to me does not look like this is an agent that is headed down the pathway for a rapid resistance development, it is looking ddI-like to me, and it is looking like another active agent for treatment-naive, and I think we will end up back, or Dr. Wong is, in about two months.

DR. GULICK: Dr. Tebas.

DR. TEBAS: I agree that I suspect that is what is going to happen, that biologically, it is going to work in naive patients. The issue I think with the label, as somebody pointed out before, is not for physicians. People will use these drugs however they want. It is for marketing. How this drug is labeled is going to determine how this drug is going to market.

If we have a broad indication, it will be marketed for naive people. If we have a restricted indication, the FDA is putting that restriction in the company for a more narrow indication. That is the decision that we are making here.

I think it makes perfect sense, this drug. If somebody wants to take a bet, I think it is going to work fine in naive people. When I see the data, I am ready to--fortunately, I don't have to give a vote, because I only have to talk here, but if the FDA approves it for a broader indication, we know that it is going to be marketed for naive people, and I would like to see the date before giving that vote, so I will restrict it, and as soon as there is data, my vote would go to give a broader indication.

I think once-a-day drugs are needed, and this is the next big wave, is going to be once-a-day regimens, and this drug could be potentially very, very good for naive people. I want to see the data.

DR. GULICK: Again, this isn't a formal vote, so we will go to Dr. Munk.

DR. MUNK: I support the broader indication based on the Agency's prior practices. I would like to raise one potential risk, which is that, kind of echoing something that Dr. Kumar said, while some state ADAP programs and payers may have no problem reimbursing off-label use, if, in fact, the drug is given a more restricted indication, that may deter some state ADAP programs or other payers from adding the drug to their formulary, and thereby make it less accessible to the very patients we are trying to make it accessible for.

DR. GULICK: Dr. Sun.

DR. SUN: At the risk of complicating the discussion, can I ask a question about a possible way out here?

[Laughter.]

DR. SUN: Is it possible to have a relatively unrestricted indication statement, but to have a caveat, just as we do for the part about clinical efficacy, in other words, have a statement that says there is currently no data in naive patients?

DR. STRUBLE: Yes, I think that is one of the approaches that we can take. The Agenerase label actually has an indication for the treatment of HIV infection, and there is a caveat there saying that there is no data in PI-experienced patients. So, that goes to the usage part of that, and we can clearly work with that, too, you know, put usage statements along with the indication.

DR. GULICK: Dr. Sun, do you want to plunk your nickel down?

DR. SUN: That is where I am putting my nickel.

DR. GULICK: That was a broad indication with some caveats, is that what I heard? As Chair, I can also express opinions here. I think that I have every expectation, too, based on the data we have seen, that this drug will work in naive patients, but I am concerned that the risk-benefit ratio may be different than experienced patients, and I am uncomfortable based on the little data that we have seen to agree with the broad indication.

So, I would vote to restrict the indication are present pending the results of future studies.

For those of you who are keeping count on this unofficial vote, we had 9 votes for limiting it to the indication for treatment-experienced, 7 votes to recommend a broad indication, and we excused Dr. Bone from voting.

And Dr. Lukert--oh, gosh.

DR. LUKERT: I am in the same position as Dr. Bone. It is outside my area of expertise.

DR. GULICK: Perfect. Two abstentions. I think this is clearly what it represents to the Agency that the committee itself is nearly split on this question.

DR. STRUBLE: I think we did get some useful suggestions that we can craft an indication, thank you.

DR. GULICK: Let's move to Question 2. For the committee's benefit, Questions 2 and 3, we are going to rely heavily on our outside experts and members of the committee with particular expertise in these areas. That is not to say others can't make comments, but I am going to start by referring to the experts in each of these fields since they are rather narrow.

Question 2. Please provide your assessment of the preclinical and clinical data with regard to bone effects. Are there additional nonclinical or clinical studies that the applicant should conduct to further evaluate tenofovir- associated bone abnormalities?

Dr. Bone, perhaps we could start with you.

DR. BONE: Thank you. I am sure Dr. Lukert and I both appreciate the opportunity to participate in this meeting, which in every other respect is a little bit outside our usual area.

I think it is fair to say we have a clear signal from the animal studies that there is a potential for toxicity, and I don't think it is resolved completely whether this is primarily a renal effect, as may well be the case, with bone consequences, or whether we have rigorously excluded the possibility of a direct skeletal effect, but I think the information we have indicates there is an effect on mineral homeostasis and that we have skeletal consequences. At least that would be I think fair to say based on what we have so far.

We have evidence that there is a problem. There is an indication that this is not a severe problem in the clinical trial as it potentially might have been based on the animal studies.

The bone density data and fracture data are only somewhat comforting because if we had seen a problem based on the very limited short-term, small number of patients, we would have really been in trouble.

To give you an idea, we typically, in order to detect a 50 percent difference in fracture rate, we will have a trial of several thousand subjects over several years for an osteoporosis trial. So, the fact that we have not seen a difference between the groups at this point is only very limited as far as how comforting it is, although it is certainly good that we haven't seen anything more than we have.

The bone densitometry data that we have is of interest, but as you heard from the discussion with Professor Genant and myself, it doesn't really address cortical bone as directly as some other sites of examination would, and so there is more to be done there, and that should be incorporated into ongoing and future clinical trials.

I think there are a number of unresolved questions that could be addressed actually, to a certain extent, out of information that is probably in freezers or potential information that is in freezers.

It is at least somewhat unclear whether we have thoroughly examined the question of whether this is a renal effect on 1-alpha-hydroxylation.

I will just take a moment since we are being asked to really address this. As Dr. Teitelbaum pointed out, one of the important causes of a mineralization defect is an insufficient level of ambient mineral to mineralize the proteinaceous matrix.

We do have one example at least or actually more than one example of drugs that directly affect mineralization, however, without lowering the serum phosphorus, and detidronate is an example of that, that is a drug that is actually still on the market, but more likely in this case, this is an effect on mineral homeostasis.

There could be an effect on GI absorption and tubular reabsorption of phosphate as postulated, that is a direct effect, and I think this needs to be investigated further.

But some evidence was given that there was a decreased level of 1,25-dihydroxy vitamin D, it is 1-alpha-25-dihydroxy vitamin D.

Remember that the kidney is principally responsible for the 1-alpha-hydroxylation of vitamin D to its highly active form, and that this is usually regulated by the serum phosphorus level and, more importantly, in most clinical situations by the parathyroid hormone level.

If the drug has an effect on the kidney that inhibits 1-alpha-hydroxylation of vitamin D, you would expect to see a rise in the parathyroid hormone level as calcium absorption would be impaired as a result of a lower 1,25-dihydroxy vitamin D.

This is the phenomenon that we see in patients with renal insufficiency of the usual kind. Also, there is a feedback relationship between the 1,25-dihydroxy vitamin D level and parathyroid hormone secretion, so there is two feedback loops.

The consequences of parathyroid hormone going up include increased phosphate secretion, so in the situation in which there is evidence of an increased parathyroid hormone level, that may be at least partly accounting for the phosphaturia and in some cases drop in the phosphate level.

Now, I don't think that we can answer all these questions today, but at least this is one of the things that needs to be really exhaustively pursued. It seems to me that from what I have been hearing, that this is going to be a very important drug for treatment of HIV, and it would be a pity if we were unable to use it to its best effect because we didn't fully understand this particular consequence of using the drug.

The possibility of a subtle long-term effect in adults is certainly something that needs to be borne in mind, and it seems quite likely from everything we have heard that if we understood the mechanism well, we could probably monitor whatever needs to be monitored with relatively simple, relatively inexpensive, completely non-invasive clinical tests, so that if some compensatory mechanism like giving a little phosphate or treating with one of the drugs that is 1-alpha-hydroxylated as a vitamin D analogue, could be employed if needed, and it wouldn't even necessarily mean the drug had to be interrupted if we just understood what was the issue.

Another point here is that there is a discussion about--and that is something, as we say, that with long-term use and large numbers of patients, something might emerge that we could head off.

The other point is the use in pediatrics. Growing bone is obviously much more vulnerable to effects of abnormal mineralization. The pediatric version of osteomalacia, for those who might not be familiar, is rickets, and this is a situation in which the bone isn't rigid enough to bear weight without bowing, and it causes the other consequences of rickets.

I don't mean to imply that this drug is going to cause rickets in children, but I think that it is important to understand the mechanism before we get too far down that road, and to know whether, for example, the dosing margin of safety is adequate.

As I mentioned, I think that some of the specimens in the freezers may actually help elucidate this from even the completed trials, and obviously, these are all considerations, many of which have been taken into account in planning of the ongoing and future trials.

I think there are two things that I would suggest that can be studied both in animals and in humans. One is sort of an intensive mineral metabolism study which could be done in a subset of the clinical trial population and also could be done in experimental animals to look at calcium, phosphorus and magnesium homeostasis absorption and excretion, and the effects on parathyroid hormone and the effects of parathyroid hormone in that context.

I think, for example, tracers could be used in animals that are affected in this way to see if phosphate absorption really is impaired in the gut, and there are a number of ways. I am not the very best expert for that either, but that is something that can be looked at to see if the hypothesized defect in phosphate absorption is really quantitatively important in this situation or not.

I think that cortical bone monitoring, as I mentioned earlier, might be more informative or at least as imformative as some of the other sites. I certainly wouldn't use it to their exclusion in clinical trials, but if it did turn out that cortical bone monitoring with a forearm measurement were useful in clinical practice, that is less expensive, easier, faster, and so on, than the axial bone density measurement. It might be a great advantage.

I think that is very important that all of these measurements could be studied in clinical trials including let's say more extensive monitoring of excretion rates of the various minerals I mentioned.

I am sure Dr. Lukert will have a lot to add.

DR. GULICK: Dr. Lukert, if you can hear us?

DR. LUKERT: Yes, thank you. I certainly agree with everything that Dr. Bone said. I am not very comforted by the lack of change in bone density measurement because bone density isn't a sensitive marker for bone changes in osteomalacia like it is for osteoporosis, and we certainly have to look at it over a long period of time and even over a long period of time you may not see the fall in bone density of patients with osteomalacia.

I also believe that we have a great need for some histomorphometric studies, because if we had histomorphometry in the monkeys that had--

DR. GULICK: I am sorry, you are fading in and out on us.

DR. LUKERT: [Inaudible.] I would be more reassured if we didn't see osteomalacia in that group.

DR. GULICK: I am sorry. Could you repeat your last point, because I think we missed it?

DR. LUKERT: I am sorry. Can you hear what I am saying?

DR. GULICK: I can now, but you are kind of fading in and out.

DR. LUKERT: What I am saying, if we had bone histomorphometry on these monkeys, who were on doses of the drug four times those of humans, then, I would be much more comforted if we didn't see osteomalacia in that group.

I think that we don't know anything about even histology at that higher dose. It makes it difficult to say you actually see osteomalacia in the human dosage.

I agree with Dr. Bone that we desperately need 1,25-dihydroxy D levels, and we need to know whether this is a direct effect on bone or mediated through phosphates, and that is why I think the bone histomorphometry is extremely important.

The problem is that osteomalacia is such an indolent, smoldering problem that you can see severe bone problems before you see the fall in the serum phosphorus or the rising up of phosphatase.

They are all problems that can be dealt with, but I think they have to be addressed.

DR. GULICK: Any other comments, Dr. Lukert?

DR. LUKERT: I think at this point that we really don't have a good idea at all what the toxicity is of bone at the doses that are being used in humans. I really think we have to settle that problem.

DR. GULICK: Thank you. Dr. Bone?

DR. BONE: I was just going to ask Dr. Lukert what she thinks about studies in children at this point.

DR. LUKERT: I think I would be opposed to studies in children until we see what the effects in adults are. Just as you pointed out, children's bones are so much more susceptible to any of these adverse effects.

DR. GULICK: Dr. Struble or Murray? Sorry.

DR. MURRAY: I just want to say that when the expanded access program opened up, we have gotten numerous requests for children. Children typically in the United States have had lots of drugs, and they need drugs or they will die of AIDS, which is unacceptable, and I think that there is probably a tradeoff where the possibility of maybe some bone toxicity or succumbing to their disease, that can be dealt with.

When it is approved, it will be used in children. If we don't study children and find out what dose is appropriate and what dose is similar to adults, then, it might be likely that children will get higher doses, putting them at more risk for bone toxicity.

So, I don't think that there is any way that we cannot proceed with careful studies in children. It is going to start with the NCI. It will be a reality. We need this drug for adults. It will be used in children. We have already had to give exceptions for expanded access in children.

At first, I was one of the proponents of saying withhold in children, but then when expanded access opened up, I knew that the cat was already out of the bag, and I think it is something we have to deal with.

DR. GULICK: Dr. Englund, a follow-up comment?

DR. ENGLUND: I would just like to say as a pediatrician we absolutely, definitely need some salvage protocol drugs for our kids who are aging into the teenage years and are resistant to everything. That is number one.

Number two, I think we could turn this question around and we might be able to get an answer out of children before you get it out of adults, so we could use this in a controlled manner to do the studies, not the bone biopsies, but measuring the vitamin levels and the phosphorus, and we can get 24-hour clearances and things like that.

I think that maybe we could even get an answer out of growing children faster than we could out of adults anyway, so I would propose that it be used under a study situation, but we need to get the answer.

DR. GULICK: Dr. Bone, a follow-up comment?

DR. BONE: I take your point about the urgency of treating, and I am sure Dr. Lukert does, too, about the urgency of treating the children with this disease. I think that you will find that the balanced studies and homeostatic studies are not as easy in growing children because they tend to be in positive mineral balance, and it is hard to predict by how much an individual, and particularly in a sick child.

What I think this does, then, is sharply focus the point that everything needs to be done to get all the information possible from prior studies and from animal studies, and the rather vague response that we have as far as what is really available in the way of information about vitamin D metabolites, and so forth, just must be focused very sharply and immediately, but I really think that that information can be extracted if the samples still exist.

The response that I got to the question about that was that we didn't have adequate baseline samples, but this was from a controlled study where there was a placebo group in animals and also in humans.

So, it seems to me that while it is always nice to have a baseline group, if you have a good control, it may not be fatal to not have good baseline data, and this just has to be extremely high in priority, and I, while quite taking the point that the urgency of treating children is great, I think neither Dr. Lukert nor I were suggesting that we should not treat children. I think what we are saying is you had better figure this out before you get very far down that road, and that means get busy.

DR. GULICK: Dr. Tebas.

DR. TEBAS: First, I want to say a caveat. I am not by any means an expert in bone disease. I am a physician that happened to make an observation.

I think what is needed in this regard is longer and larger trials, and I think 903 is a good trial. I suppose it will also give the opportunity to find patients with--if something is going to happen, those patients that develop the problem with the most severe phenotype could have a bone biopsy, and those patients would provide a lot of information to the bone experts to figure out what is exact effect of this drug, if it has an effect on bone metabolism in adults.

So, I think 903 is a good opportunity, and if somebody, and if the company sees somebody developing an unusual phenotype, those biopsies should be pursued to try to obtain the maximum information from those patients and not going back later on to try to obtain that data.

DR. BONE: I think as Dr. Lukert pointed out a moment ago, that biopsies would probably show an abnormality before the phenotype was expressed clinically or by laboratory results. Would you agree, Barbara?

DR. LUKERT: Yes, I would. I just think that testing is critical. We could use it rather quickly.

DR. BONE: The mineral homeostasis study should be very short term.

DR. GULICK: Dr. Yogev.

DR. YOGEV: Obviously, I am not a bone expert at all, but just one observation. I thought that the newborn, the way it grows is different than adolescent, different than at 6, 7 years of age. The reason I mention it, I am a little bit concerned that the study in pediatrics go from 6 months to 17 years of age, and from my experience in the past, there are drugs who are approved, for example, from 6 months on with three kids or four kids below the age of 2 years, and I think the bone in that population is so different, and especially in the newborn, I don't understand why we stop at 6 months, we don't go to the younger population, especially we are seeing more and more resistance.

So, this one point, that studies in children should be devised better with a bone expert, do we need to separate to a different group. The other point is many of those studies are done in Europe and in United States, and those children from the bone mineral, the vitamin D are different than the people in developing countries, that a high percentage of them are vitamin D deficiency, have other problems, that we need to put caveat to that, that we need to see studies in this unique population already has the bone potential impairment because those drugs should be also aimed to the 10 million kids at this point who are HIV infected.

DR. GULICK: Dr. Tebas, a follow-up comment?

DR. TEBAS: Dr. Bone, you are the expert. Would you suggest doing a bone histomorphometry study in a selective group of patients that don't have like with tetracycline labeling and after being exposed to these drugs for a long time, to study mineralization to see if there is an issue or not?

DR. BONE: Well, there may be some issues related to the biopsies, but this is something that we do for every drug we study for osteoporosis, and even in those cases, those are drugs that have been very thoroughly studies preclinically. I think the first question is what is going on in the monkeys at moderate exposure dose, a 4-fold exposure.

Maybe Dr. Lukert would also have an opinion about biopsies in patients who are not necessarily symptomatic, but in adults.

DR. LUKERT: Yes. I really would like the issue addressed to the monkeys, because I think it might really settle some questions. If those were normal at doses 4 times what are used in humans, I wouldn't be so concerned, but I think that maybe you could pick the subgroup of people who did have any subtle biochemical abnormalities like the people who become hypophosphatemic, and biopsy those people.

Certainly, if those people were absolutely normal, I think you could put some of these concerns to rest.

DR. GULICK: Dr. Munk.

DR. MUNK: I am kind of growing increasingly concerned as this discussion proceeds, and I believe it was Dr. Lukert's term that osteomalacia would be a smoldering problem, and unfortunately, people living with HIV and taking anti-HIV medications are subjected to an ever lengthening list of smoldering problems, so I would strongly urge the sponsor to figure out, if possible, the best way to get an early read on whether or not this problem is occurring, and to maintain follow up of a large number of patients for a very long period of time to monitor the extent of the problem.

DR. GULICK: Yes, Dr. Goldberger or Dr. Birnkrant, either one.

DR. BIRNKRANT: I was wondering if you could recommend, though, at this point, a standard battery of testing and how often these tests should be performed in patients receiving tenofovir DF.

DR. BONE: You are talking about not study patients, but patients in clinical practice?

DR. LUKERT: I would say every three to four months, because that is sort of in sync with a bone remodeling cycle, probably looking particularly at the phosphorus and the parathyroid hormone levels and the calcium.

In the beginning, the 1,25-dihydroxy D levels until we know what is going to happen to those. Of course, we are going to assume that we would have 25-dihydroxy D levels on all of these patients to make sure that we aren't dealing with a vitamin D deficiency.

DR. GULICK: Dr. Bone, I am not sure everyone in the room heard that, if you want to repeat.

DR. BONE: Well, I agree with Dr. Lukert that we would want to, at intervals of about three to four months, measure the serum calcium, phosphorus, and alkaline phosphatase levels. I think we would probably want to measure the bone specific alkaline phosphatase level because there are apt to be other reasons, not the least of which would be hepatitis, that would alter the total serum alkaline phosphatase level, and might be confounders.

We would want to measure the intact parathyroid hormone level, 25-hydroxy vitamin D, and 1,25-dihydroxy vitamin D at baseline to make sure that we didn't have a baseline abnormality. 25-hydroxy vitamin D is the best measure of the adequacy of vitamin D nutrition, and we usually find that levels of around 30 nanograms per mL or higher are associated with a good vitamin D status, lower levels which fall within the normal range for the laboratory may still be suboptimal.

The 1,25-dihydroxy vitamin D is an issue that has been raised here, and there is a possibility that its production is impaired, and that would presumably have a reciprocal relationship with the parathyroid hormone level.

I would agree with those recommendations. I think a baseline bone density measurement including the forearm is probably reasonable because you are obviously going to be more concerned about patients who have low bone densities, but as Dr. Lukert has pointed out, the central bone density is a very poor way of detecting this problem and were not very sensitive.

I think another pretty obvious thing to do is to make sure that the patient's calcium and vitamin D intake is adequate according to general recommendations, because it would be ridiculous to impose a very well-known problem on this obscure one by not making sure that everybody had sufficient calcium and vitamin D intake. That is only a couple of pills, but it is something to take into account.

DR. GULICK: Dr. Pomerantz, the last word.

DR. POMERANTZ: No, no, it is not going to be the last word. I was going to ask Dr. Bone to have the last word, because I am a little confused with that.

Upfront, what are you going to get on these patients, what would you recommend, the exact tests that you would get when they come in, before they start on the drug?

DR. BONE: If you send me a patient and said you have a patient you were planning to start on this drug--

DR. POMERANTZ: Precisely.

DR. BONE: --I would get just what I just listed.

DR. POMERANTZ: Do you want to list them again for me?

[Laughter.]

DR. BONE: Okay. Barbara, please chime in. I may add one or two things. I think we would get a serum chemistry panel that included calcium, phosphorus, and alkaline phosphatase level. I would add probably a bone-specific alkaline phosphatase level.

We would measure the baseline 25-hydroxy vitamin D level to make sure the patient was vitamin D sufficient before starting therapy. It is easy to fix if they are not, but you wouldn't want to initiate the therapy until you were sure that they--at the very least, you can just give a vitamin D injection that is good for several months. There is a depo injection.

We would get the parathyroid hormone level and 1,25-dihydroxy vitamin D levels to make sure they were all right to begin with. It would make a lot of sense to get a baseline 24-hour urine collection for calcium, phosphorus, creatinine, and sodium.

What we are doing here is the equivalent of a clinical trial, because we don't have the clinical trial data. This is the kind of information you might very well not need later on.

DR. POMERANTZ: You would do this on every patient that we start this drug on?

DR. BONE: Well, if you send me a patient and said you wanted to have their risk of osteomalacia characterized and me to help you monitor them, that is what I would do.

If we don't get this information, then, you won't know what is going on.

DR. POMERANTZ: So, you have these seven things upfront.

DR. BONE: Right, and I think there is an argument to be made for a bone mineral density measurement, as well. I don't know that that is absolutely essential for the reasons that Dr. Lukert mentioned, but there is a case to be made for them. I wasn't asked to come to this meeting with this exact set of recommendations for clinical practice, but that is what Dr. Lukert said pretty much.

DR. POMERANTZ: All right. That is upfront. If you don't mind, Trip.

DR. GULICK: Go ahead.

DR. BONE: Just a second. Dr. Lukert, did you disagree with anything I said?

DR. LUKERT: No. As we said, if these had been settled in the clinical trial, you wouldn't have to do this in all these people, but I do think that every single person would have to have vitamin D deficiency ruled out, because these are sick people, and we know that even in well people, the incidence of vitamin D insufficiency is around 10 percent, and in sick people, it is somewhere between 20 and 40 percent.

DR. POMERANTZ: So, we have these seven and possibly eight things upfront. Then, what do you measure every three to four months now?

DR. BONE: I think Dr. Lukert's recommendation, with which I agreed, was we would follow the calcium, the phosphorus, the alkaline phosphatase level, and the 1,25-dihydroxy vitamin D and parathyroid hormone.

DR. GULICK: It is worth pointing out we are talking about how you assess these abnormalities on a clinical trial versus what might be done in clinical practice.

DR. BONE: I think what the question was, what would we do in clinical practice absent clinical trial data, and that is the answer.

DR. GULICK: I think that has led to some confusion, I think among people around the table about what we are recommending to be evaluated, that needs to be done, and then assuming we have that information, what we would actually recommend for safety monitoring in the general clinic.

DR. BONE: Well, I think once you know the answer to those questions, and have a mechanism for this problem, you would probably simplify the list, but what the list would be, would be dependent upon what the answers were to those questions for which we don't have the answer now.

DR. GULICK: Understood. What you are saying is we need the data before we can really make a clinical care recommendation.

DR. BONE: Right, but if you are asking me for a clinical care recommendation without that kind of comprehensive data, I would say you pretty much have to follow those patients on almost the same way that you would if they were in a trial.

DR. GULICK: Dr. Goldberger.

DR. GOLDBERGER: Given the comments of the last few minutes about bone toxicity, monitoring, et cetera, I was just wondering whether any of the committee members, guests, et cetera, had any other observations to make about what we discussed a few minutes ago, i.e., the broad versus the narrower indications.

DR. GULICK: Do you want to change your vote?

DR. STANLEY: Yes. It was just occurring to me that we have essentially now restricted its use, because I am not going to use it in a treatment-naive patient if I have got to do all this stuff upfront.

DR. JOHNSON: I think if we had done Question 1 last, I am very conservative, and I want to restrict now.

DR. GULICK: It's a good thing we didn't take a real vote here.

Dr. Tebas.

DR. TEBAS: I just wanted to point out that this is advice for the company. I mean we need that in clinical trials. This has been used in more than 500 people for a year, and there were no abnormalities seen in phosphate, phosphaturia in a significant proportion of patients, so I think this needs to be done in the setting of a clinical trial. I mean I don't think we should recommend these for the whole population before we have that data from the clinical trial.

For a year, the abnormalities were not detected in the trials that have been done so far. I think these questions have to be answered in the setting of a clinical trial, and not start doing these parameters in basic clinical HIV practice like mine.

DR. GULICK: Again, I think what is going on around the table is that we are revisiting the issue of risk-benefit between naive and experienced patients and where we have the data about these abnormalities, we do have a lot of data in the experienced patients. People are getting a bit more concerned that we simply don't have the data in naive patients, and what would an appropriate way to be to collect the data on a clinical trial setting.

Dr. Munk.

DR. MUNK: Another question for Dr. Bone as to whether patients with renal insufficiency would warrant special attention.

DR. BONE: Well, of course, but I mean you have got a confounder there that most patients with renal insufficiency will have an abnormality of vitamin D metabolism and parathyroid hormone that is similar to what has been described here, but they will have decreased phosphate excretions, so if the problem here is really hypophosphatemia, they will be self-cured.

I think that Dr. Lukert's point, the most important single point here probably starting a patient will be to make sure that their baseline vitamin D status is okay, that they are not starting off with a problem related to this.

You asked us what the optimal regimen was for monitoring, and we told you what we thought was the optimal way of monitoring. Now, whether you are going to do that in every single patient is a judgment you are going to make.

The information we saw from the clinical trial, that was rather limited, but, you know, it wasn't a flashing red light here, but we have got this sort of unresolved question.

I suspect that some of this information, some of the concerns we have can be resolved sort of out of inventory, if you will, of information that could be developed from studies that have been completed and are ongoing rather quickly, but make sure you don't have an underlying problem before you start.

DR. GULICK: We are going to need to move on. I will take two last comments from Drs. Yogev and Pomerantz.

DR. YOGEV: Mine is very quick. Clinical studies, what about pregnant women, is there anything specific that you should test most specifically?

DR. BONE: I don't think we can make any specific recommendation about that. What have you got in the way of data in the animals, the fetal toxicity data?

DR. YOGEV: I was referring to the women itself.

DR. BONE: You are talking about the women or the fetus?

DR. YOGEV: The women.

DR. BONE: Obviously, it is a challenging environment for both mother and the baby at that point because you have got a lot of mineral mobilization for the fetal skeleton, so they are both at risk if there is a problem.

DR. YOGEV: Women are 25 percent of the epidemic, we see more and more kids interested, in preventing the infection, so that is another clinical portion that needs to be added.

DR. BONE: I don't know what Dr. Lukert feels, but it is possible we could, with more information from the trials that have been completed than have been exposed to, make a narrower set of recommendations. I don't know that. We are obviously both trying to give you as comprehensive set of tests that you might do, having been asked the question and the way we work.

DR. GULICK: We appreciate that.

Last comment, Dr. Pomerantz.

DR. POMERANTZ: Probably it is my last comment ever at this committee. The comments by Dr. Bone and Dr. Lukert, I think are an important point and show when you don't have data for the virology, you are usually compounded by risk-benefit as you learn a little bit more about the drug, because you didn't vote, you guys, on the original, but yet you added something that I think changed the context of this, I think even with a lot of the people who might have used it upfront before these discussions.

I am certainly not going to argue with you on what tests should be obtained, but I do think that it adds yet a third empty data set for using it in naive patients, what happens with high viral loads, what happens in naive patients, and now what happens with the possibility of generating osteomalacia with a panoply of tests that are going to be hard to explain when you have other options for patients who are naive.

DR. BONE: That is all taken in the context that osteomalacia is something that is less serious and a lot more easy to fix than HIV. So, you have got to remember what your original purpose was here, of course, as well.

DR. GULICK: So, let's summarize this portion just briefly. In terms of impressions about the preclinical data, Dr. Bone really summarized that by saying that there was a signal for safety issues in animal studies.

Moving to clinical, again, summarizing saying that based on the data we have, the safety issues do not look severe although there are still quite a few unanswered questions, and as came out in the last couple minutes, particular populations where we simply don't know what the safety issues are, naive patients, renal insufficiency, children, pregnant women.

We have limited data based on fracture and densitometry information, but got cautioned about that data, that it really may be preliminary to make conclusions based on the amount we have.

In terms of future studies, the strongest recommendation was to identify what the mechanism is here, is it primary renal effect versus direct effect on bone. We got the suggestion from a number of people that long-term and larger follow-up studies are key, and as an example, the 903 study which was up there a minute ago, is one such example of that kind of study.

We talked about pediatrics, that risks and benefit ratios, particularly in advanced HIV disease, may be tipped one way or the other, that there is certainly a need for drugs and data in this patient population group.

A number of studies were suggested that might be looked at, follow-up fracture, densitometry, biopsy studies, cortical bone monitoring, mineral metabolism studies, and then towards the end we began to talk about what might be done to completely characterize this problem, and then jumping from there, what might be recommended in routine clinical practice.

As Dr. Pomerantz ended with, in a sense, the committee really began to reassess the risk and benefits given the unknowns about this particular problem.

Let's move forward to Question No. 3. Please provide comments on the clinical resistance analyses conducted during the development of tenofovir, provide recommendations for the types of clinical virology analysis that should be conducted for future antiretroviral drug development and suggestions for the type of resistance data and analyses warranting display in package inserts.

So, the three issues are let's comment on the resistance data we saw for tenofovir, and then number two would be jumping to the future, what kinds of resistance information would we like to see for new drugs, and then come back to what kind of resistance information should be displayed in the label.

Again, we are going to rely on our experts. Dr. Johnson, shall we start with you?

DR. JOHNSON: I wrote out some comments, if that is okay. I will be brief. I think Gilead is to be commended again for the extensive phenotypic and genotypic data analyses that were presented, as the FDA, and Gilead beautifully pointed out, all of the data are limited by low numbers, and this is what we face all the time, making definitive statistical conclusions difficult, especially broken out by specific mutations and combinations of mutations as expected in analysis of real world clinical isolates, displaying tremendous heterogeneity.

The pooled analyses are what should be evaluated and considered for package insert presentation. We saw more genotypic results and phenotypic results partly in fact because of the low load, but as other patient populations are studied, we should be able to get more information.

Jonathan Schapiro pointed out in an excellent fashion that we really would like to see I think a little bit more dissection at a mechanistic level of the patterns of resistance emergence and the stepwise accumulation of mutations, and perhaps there are different pathways.

I think Dr. Miller plans on exploring that. That is somewhat analogous to what was done with abacavir. That doesn't impact on package insert labeling, but it is just one of the clinical virology studies that we desperately need to see to understand does this occur in a stepwise fashion, is it an on-off sort of resistance, can you expect ongoing accumulation of other resistance mutations beyond K65R, which leads to the next point.

All of the short-term analyses over 24 weeks would not in a setting of multi-drug therapy be expected to yield large frequencies of emergence or development of resistance mutations, and we really need longer term data, larger numbers of patients, just as is planned in some of these larger studies, but 24 weeks is not enough to be certain. We heard this glimmer that there were only--I wrote this down--only a few more accumulated, two more week 96 accumulated, a K65R, which to me is one of the ddI-like mutations, and I was rather encouraged by that.

We heard in the initial presentations from Gilead that K65R emerged, and we also heard what I think needs to be kind of removed from Gilead's language and labeling languages, unique resistance profile, and Gilead themselves, and I think what everyone would agree that, for example, the K65R mutation is an RT mutation that is associated with resistance to ddC, ddI, and abacavir in vivo, and it is selected by tenofovir in vitro.

I just brought along our ISU and say June 2000, mutational patterns and showing the overlap with K65R among various drugs in the RT class is another point that I make, that basically I don't know that this is not just another RT inhibitor albeit one that should be in our armamentarium and is active.

The reason I say that is whereas previously the in vitro work, the tenofovir was shown to be active against NAMs, the nucleoside resistance mutations like L74V, T69D, two or more of the ZDB associated mutations, and the Q151 and multi-nucleoside complex.

We have been shown elegant data by Gilead that there is some potential for cross-resistance in vivo between tenofovir and abacavir, ddI, D4T, ddC, and AZT, and that was shown in the nice way that the FDA pooled the data presented them by the NAMs presentation, where the greater number of NAMs with the 41 and 210 caused some attenuation of the clinical virologic response.

Notice that we saw some Virco data for the phenotype still looking like tenofovir was fairly susceptible, which again I found fairly reassuring, but I want to get everybody thinking, as somebody who has gone to every resistance meeting since they started having them, that drugs, even within the RT class, at subtle levels that we don't yet understand mechanistically can contribute to development of resistance and broad intraclass resistance, and perhaps that will happen with tenofovir, not to thwart its approval for salvage, just to make us more vigilant to monitor carefully, to continue to do, and to compliment Gilead again on the extensive, high quality phenotypic and genotypic studies that they have done.

I think I will finish with a point that gets to the third thing, is what should go on the package insert. Obviously, discussions about what happens with tenofovir alone with regard to K65R, genotype emergence, because people in the clinic are ordering this drug resistance test they will need to see that and to understand that the increase with regard to the 4-fold and tenofovir susceptibility knocks out response. That needs to be in there just for tenofovir alone.

With regard to cross-resistance, we would like to see perhaps a table that did get to, if you have got three or four NAMs with 210 and 41, X percent of the patients might have an expected virologic response. I think that will be very helpful. I realize that is unprecedented for the FDA.

I looked back and brought the abacavir package insert even though they have got similar diminution of response even particularly in the setting of 3TC and AZT with backbone nucleoside mutations that we are in a different era, it is 2001, people are ordering resistance tests, and the question they are going to ask in salvage is to save money, cost, toxicity, whatever, will this drug have a chance of working in my patient. That is just another thing to consider.

I think I will stop there except to again maybe bring us back to something I raised earlier this morning, and something that I believe one of the community people raised is what is the role of 3TC and the M184V, and my read of this again was that that enhanced activity was lost when 70 percent of the subjects had a NAMs present, making if it could possibly be on the label, I think the clinicians want to know do I need to continue 3TC or not, some presentation of that data, letting the people decide whether they think that it will work or not, to leave it in the regimen would be helpful. I will stop there.

DR. GULICK: Thank you.

Dr. Struble and then Dr. Schapiro.

DR. STRUBLE: So, Dr. Johnson, I guess you are in favor of putting as much resistance information in the labeling as possible even though that some of these mutations may be based on a small subset of patients and putting the appropriate caveats, is that what you would like to see?

DR. JOHNSON: Yes.

DR. GULICK: Dr. Schapiro.

DR. SCHAPIRO: I would agree with Dr. Johnson's comments. I would also start by saying that I also think that we had some very nice virology data. I think the folks from Gilead should definitely be congratulated. These are both expensive and smart studies, and I think that definitely we have seen much more than with previous drugs, and I think that is very important.

I think also the folks from the FDA, both have the last couple of years made a big effort to bring resistance to the forefront. I think this drug and the previous drug that was discussed both have much more than in the past, and I think it shows some cause and effect, that by bringing this and discussing it, we are getting better resistance data.

As Dr. Johnson said, not long ago we weren't seeing almost any of this. I also think the analysis that was done was very helpful that Kim presented.

I will answer the three things together. I think that the resistance, it is important that we not take a step backwards. We know resistance is not a dichotomy, it is not yes or no. There is a reduction in sensitivity that we see which requires additional drug. That is how we look at resistance, and it is very, very important not to go back to saying yes or no resistance. There is no such thing.

There are reductions in sensitivity, and we saw data presented in that way, and we should not find ourselves lumping data to get statistics, and then lose this effect. I think that the minute the study, the large study that most of the data is coming from does not allow patients with high viral loads. We are not going to get enough data. Those are the patients with the mutations.

The minute I think any of us saw that the patients had 400 CD4 and 5,000 viral load, we knew we were not going to get enough to get correlates, and I think it was understandable that to enroll those patients we needed that, but I was not surprised that we don't see mutations.

We know, Vicki and I look at resistance assays. There are a lot of patients with five or six NAMs or TAMs, and there are almost none in this study. We see those every day. So, when you limit it, we didn't have any chance of getting enough mutations because of all these different combinations.

So, I think that in the future, it would be very important to somehow, yes, enroll patients with mutations in order for us to have enough. I also think that what is missing is the correlates between specific genotypic patterns and the phenotypic change.

Articles have been published. There are panels now of isolates, both clinical and laboratory, which are tested in a standard way, and that gives us a lot of insight. So, I think that is missing from the data set.

I think that in future studies, we have to delineate the issue of 184. It is surprising that some very convincing in vitro data was not supported. The data here does not support that clinically it panned out, and that is curious. It is also key because the clinical question which came up a number of times this morning, do I continue 3TC or not, will come up and that is very important, and it may come up for abacavir and other drugs, as well. So, that should be looked at.

Regarding the label, I think it is key to show as much information as possible, and I think in this case, even though we do not have statistical significance, we want to show the tables. I think Table IVE, that Kim showed, and actually IVD, those are the two summary tables are very important and they are key, and whether we got statistical significance or not is unfortunate, but I think often we don't.

I think we have to remember that both genotypic and phenotypic assays are now being used routinely. In order to interpret these, we need exactly the data that Gilead provided us. We actually have these mutations or this phenotypic change provided this much of viral load reduction.

That is the data that we are now scrambling for anxiously with our previous drugs, and we have the benefit of the good work done by Gilead, and we definitely, definitely should include that, and I would not lump that together to get a p value. I think that would be a mistake, and I think the key would be a phenotypic assay that shows a 3.5 reduction. If you lump and use 4, that will read out as sensitive.

If you provide this data in the label, you can look and see that although there is still activity, it is less than you see if it's 1 or 1 1/2, and I would be very, very cautious not to run back to statistics and lump that together.

I think an example again, if we show slide No. 6 that was shown in the beginning, which uses the conventional cutoffs, and we have 3-fold and 10-fold, is totally irrelevant to what was shown afterwards.

So, I would show those nice tables even though they don't have statistical significance. Maybe we will have studies in the future which will, but I would not back off and lump them again together to get p values.

DR. GULICK: Other comments from the committee?

Dr. DeGruttola.

DR. DeGRUTTOLA: I also thought it was great to see all the resistance information, and I like the way the Gilead presentation made distinction between the protocol- specified analyses and exploratory analyses that were done later.

I also like the presentation that Dr. Struble made. I like the fact that all of the TAMs were listed, so that you could look at each of them individually and then look at different combinations as we have discussed.

I think one additional thing that might be interesting is to look at the proportion of the variability in response, the DAVG, that is explained by the mutation patterns, and there are a number of different ways of doing that. That obviously gives you some sense of how important the sequences are in capturing variability and how much variability is left over to be explained by other things including perhaps other mutations that haven't been looked at, as well as, of course, other factors. So, I think that might potentially be of interest.

The other thing is the issue, Dr. Struble mentioned this morning the question of what do you do about the fact that if you do formal statistical testing, you are doing many tests, so how do you adjust for the multiple testing, and I think that that is an open area of research. I don't think that has been resolved in resistance analyses. Of course, there are common statistical procedures for adjustment that are probably too conservative in this case.

This is an informal recommendation, but just a suggestion that perhaps people might want to look at other kinds of exploratory techniques like clustering and partitioning, obviously only for the exploratory analyses.

DR. GULICK: Dr. Johnson.

DR. JOHNSON: I just wanted to make one other comment I overlooked in what you would say about tenofovir directly.

If you look at Table 4.14 in the Gilead tables, as well as the FDA Table 4A, you will see that the L74B VRI substitutions, although the numbers were very small, at tenofovir 300 mg, there was really no viral load reduction, and I think you could maybe think about mechanisms, ddI is also DATP-like, mirroring the natural substrate for RT, which maybe for ddI, has been one of the reasons it is hard to develop resistance, as Doug Richmond has taught us. Maybe the same is true for tenofovir to explain this development, but we may want to put a cautionary note that having not just the K65R, but L74V or I, were likely to abrogate response, as well as ditto the T69S insertions, the Q151M, which we knew about from in vitro work.

DR. GULICK: Dr. Hamilton.

DR. HAMILTON: I don't think it would do just to hear from the true believers here. As inexpert as some of us may be, there is a large group out there who are not convinced that using genotypic, phenotypic analyses in fact do have, have been proven to have an effect on the clinical outcome of patients with HIV infection.

To my knowledge, this knowledge, as important as it is virologically and biologically, and it is interesting and fascinating and detailed as it is, has not been used to my knowledge to prevent the emergence of these resistance patterns.

Does this mean that we shouldn't provide this information to the users, the consumers of this product? No, it doesn't mean that, but it is going to change. I haven't seen an anti-infective agent yet whose resistance pattern doesn't change after it is in use.

So, if you are going to put it in the package insert, you ought to plan on changing it every so often, because it certainly is going to change. So, I am not so much arguing with the comments made by others here, but just interjecting the more general comment that I am not certain we are overdoing this issue.

DR. GULICK: Dr. Schapiro.

DR. SCHAPIRO: First of all, I think there is virologic data that these help. I don't know if we have data that this prevents additional mutations. I think we have indirect evidence because we know that reducing the viral load does reduce the generation of mutations, but I agree that we don't have outcome data for the patients. That might require longer follow up.

I do think also that, as you said, resistance patterns will change. I think we definitely are looking only at one type of resistance. I think it is evident. Dr. Johnson mentioned ddI, and I think that for protease inhibitors, as well, there are other mechanisms of resistance. Some of them may be cellular, and we are simply looking at one of them.

I think Dr. DeGruttola, one of his comments was we could quantify how much this resistance is really responsible for those changes in the viral load, and that might be important.

I think that by providing the data in the package inserts, we allow people who do want to use this to see the data. I don't think we necessarily have to, that forces them to use it, but I think it is a pity where we have this high quality data, which we don't have with the others, not to include it, and I agree definitely that we are probably in for some surprises.

DR. GULICK: Other comments from the committee? Yes, Dr. Englund.

DR. ENGLUND: I just wanted to say that for some of the resistance data, it changes so fast and those people who clinically use it, can access the Internet and have other access to things, that one of the things I would recommend is putting in the package insert something like Table 4D, which is a nice, general table. This goes any TAMs instead of giving so much specific things which are going to change in two months when they more studies done.

DR. SCHAPIRO: Just to mention that the publication that Dr. Johnson showed is actually on the Internet and is updated.

DR. ENGLUND: My patients bring it in, too. Maybe sometimes they know more than some of us. But I like the idea of for package inserts, to not know that you are going to be outdated before it comes out, I would be a little concerned about that. It is great data.

I like the idea of having a table. I like it in the package insert, but to perhaps include things that are a little more generalizable, like this 4D, which shows any TAMs instead of every specific mutation, because absolutely that is going to change, and it is going to change by the next AIDS meeting.

DR. GULICK: Dr. Sun.

DR. SUN: I would just like to make the point that I think for this kind of data, the standard should be different than that for clinical trials. I think by the nature of this kind of work, it is generally retrospective, it is exploratory, which doesn't mean it is not robust. I think you can apply robustness by doing your statistics in a robust way and doing sensitivity analyses, but I do think it is useful to have this kind of information label, if for no other reason than to try to get some standardization of interpretation for individual drugs.

I would recommend to the sponsor that whatever is in the label, you try to also have the resistance testing companies adhere to that, so that not every resistance test that is available in the marketplace, some of which are not regulated, has their own set of rules and leaves physicians extremely confused.

DR. GULICK: I will just try to summarize this part. In terms of the assessment of the resistance data presented by Gilead, the committee really would like to commend Gilead on providing extensive, high-quality data that people found quite useful.

Having said that, people raised concerns about low numbers of patients, the heterogeneity of the resistance patterns we saw, and perhaps that the patient population studied was not particularly ideal in that they had relatively limited viral load levels and high CD4 cell counts.

The information we saw was genotypic much more than phenotypic, and the potential for cross-resistance among the available drugs was addressed.

In terms of the future analyses, we mostly centered on what more we would like to see concerning tenofovir, although many of these areas could be extrapolated to future compounds also.

Dr. Johnson suggested that perhaps the most valuable information would be to really carefully characterize the pathway, the patterns of the development of resistance over time, what are the ongoing steps in changes that confer resistance.

We agreed that longer term data would be very helpful, noting that what we saw was really 24 weeks of data. We would like to see longer term data in larger numbers of patients. Again, going back to the patient population, it will be very interesting to see what kinds of patterns emerge in a highly treatment-experienced population with high viral load levels.

Dr. Schapiro called for analyses which correlate the genotypic and phenotypic approaches. Several people mentioned that we would like to clarify the M184V data, particularly for clinicians who were struggling with whether to continue 3TC or not.

Dr. DeGruttola made some suggestions about analyses that could be done, looking at variability of mutations and how to address the problem of multiple comparisons including novel techniques like clustering and partition analysis.

In terms of the label itself, people felt generally that resistance data was extremely helpful, that this was bringing us into 2001, that we really do need to update the label as the field matures with regard to providing the data that is available to clinicians.

There were several words of caution, one being that perhaps the resistance data we have will change so quickly that the label could rapidly become outdated. Also, the caution that most of the data we are seeing is exploratory and retrospective, but the general feeling, I think among the committee, was that yes, we would like to see this information.

In terms of how to portray it, people felt that they liked the table format specifically from the FDA analysis 4D, which was a summary table of the genotypic patterns, and 4E, which was the summary data for the phenotypic patterns.

There was a call for defining cutoffs if they are known, particularly for phenotype, and a general call for providing pooled data, but with inherent problems about small cell numbers in terms of doing statistics, but an urge to provide data in a way that was interpretable to clinicians, and that is going to be an ongoing battle I think to do that.

There was a caution about claiming that a drug has a unique resistance profile and that the potential for cross-resistance, among other drugs that are currently available, be outlined in the label if there is data to address that issue.

Finally, Dr. Sun led the charge that we really need a standardization of resistance information particularly if it is going to enter into labels for newer antiretroviral therapy.

Dr. DeGruttola.

DR. DeGRUTTOLA: I wanted to make one comment that may not have been clear. Dr. Gulick mentioned looking at the variability of sequences, which I think may be an interesting thing to do, but what I had intended to apply was to look at the variability in response of the patients, in other words, the DAVG or whatever the response measure is, and see how much of that variability is explained or capture by the resistance information.

DR. GULICK: Thanks for the correction.

From the Agency point of view, were there other things with this particular question that you wanted us to address?

DR. STRUBLE: No, I think we got the feedback that we were looking for. Thank you.

DR. GULICK: Got it, huh?

DR. STRUBLE: Yup.

DR. GULICK: Let's move to the last question.

Please provide comments on the applicant's proposed second study for traditional approval, and provide comments for other study designs or patient populations that should be studied as part of Phase 4 commitments.

Let's again break this into two sections. Let's take a look at the proposed pediatric study.

[Slide.]

Let's first consider this study design, which they are proposing in pediatrics.

Dr. Yogev.

DR. YOGEV: I think the most important part is I don't see on what is here, wasn't mentioned stratification of the population. I think it is completely different than the pediatric. The pediatric in the older group are very different than two years of age and younger.

We recently are finding out even if you go less than two years of age, there are differences in between the one month to the three months and six months. I mentioned before, I just want to stress I don't understand why less than six months are not included.

Maybe there is some logic in the two weeks, then stop, reassess, and do another one as in intensification versus how tenofovir in the new setup is working. I am not sure that that will give you the answers.

Obviously, the PK was not mentioned, I am not sure what they are looking for. I think this is one of the issues. We, in the past, I just hope we will not repeat the same mistakes which we did with the AZT. A lot of us still remember, many of us, that we woke the patient every two hours and then four hours and then six hours.

This drug is intracellular, and there are some data to suggest that maybe in pediatric, for some reason, mononuclear cells are more affected, a higher percentage of them are affected in the process than the lymphocytes, and when you look into the PBS results in vitro versus lymphocytes, it is interesting that is much more sensitive, that maybe you don't need that much.

So, maybe where we need to look is really to avoid toxicity of the bone, whatever, is intracellular levels in activity, which I don't see in what is recommended here.

DR. GULICK: As I recall, the sponsor has planned PK studies apart from this in pediatrics, is that not true?

DR. YOGEV: But it is an escalating dose which I presume if they go by the classical one, they try to compare it to what will happen in adult, and I am not sure that's in pediatric the right way to do it. I don't see it in this one.

DR. GULICK: Let me take a step back and just remind people why we are looking at this study design. So, this would be the second study to receive full approval, and this would be going with the 903 study, which is the study we have been talking about most of the day in naive patients.

So, this is a two-part hybrid, and I think we coined that term at this table with some help from some others. So, it is looking at a population of children, viral load levels greater than 30,000, reduced CD4 percent as outlined there, and treatment-experienced defined as having one member of each drug class.

They are on stable antiretroviral therapy and then are randomized 1 to 1 to either add tenofovir or placebo for two weeks. That is looking at the virologic activity, and then optimizing the baseline based on genotypic tests, which were--or genotypic and phenotypic--genotypic tests which were performed at baseline to optimize the background drugs, and then both are continued for 46 weeks.

So, two different endpoints, two different parts to the study. That is what makes it a two-part hybrid. Okay.

So, other comments on this design? Dr. Schapiro.

DR. SCHAPIRO: As you mentioned, this was discussed at a previous meeting. I think it is important to realize that the first two weeks are very precious, and it is probably important to get more than one viral load measurement, and that is key. I think it is important that a byproduct of this is we can get very tight correlations between baseline resistance patterns and two-week viral load outcomes, which I think will enhance a lot of the understanding of resistance.

So, I think this will give us good efficacy data, but I think it will also contribute a lot to some of the questions that Dr. Johnson and I and Dr. DeGruttola were bringing up, so I think that could be of good value, but it is important not to lose the benefit of the first two weeks even at the expense of having the kid give blood another couple of times during that period for additional time points.

DR. STRUBLE: Dr. Schapiro, how often do you think that viral load should be measured in the first two weeks?

DR. SCHAPIRO: First of all, I would make sure you have a good baseline, and what we don't want to have is zero in two weeks. I mean we can wait a second for Victor to give his opinion, as well, but I think that the caution here is an end to have a pretty good definition of where the patient started and where they went in two weeks.

In addition, there have been some studies that I think Victor may have been part of it, where the slope actually can be looked at, which you would need additional time points. I would at the very least take it one week and at two weeks, and I would be interested to what Victor thinks would be valuable as far as how many time points of viral load in the first two weeks are necessary.

DR. DeGRUTTOLA: It obviously had to do with the degree of accuracy that you want to be able to estimate that slope, and the amount of power that you require in order to make the comparisons.

Those kinds of calculations have been done, so that it is possible to see how much additional power you gain by adding additional time points. I don't have specific recommendations right now.

The other issue, of course, is if you are interested in getting any of the fine detail of the response over the first two weeks, but usually that is less of an issue than just being able to make the comparison itself.

DR. GULICK: Dr. Wong and then Dr. Englund.

DR. WONG: I have a little bit of a different comment about this. I expect that the results of this are to a great measure going to be determined, or at least in part, by how good the optimized background regimens are and perhaps also how different they are from what the patients have been receiving before.

I am a little worried that superiority of adding tenofovir might not be able to be shown depending on how good the change is from the background regimen to the new regimen.

If the null hypothesis here, well, if the hypothesis that is being tested here is that tenofovir, when added to another regimen, gives a durable result, I think that one of the things we saw here today from Study 902 is that the answer to that is yes, it does.

So, I am not sure that I would conclude, even if this study turned out to be negative, if the new study on the naive patients gives a clear-cut result for 48 weeks, and the results in 902 really pass FDA review when all of the data can be scrutinized, that I might not conclude that the hypothesis has been shown whether or not this happens.

Now, that is not to say that I don't think this study should be done, because we clearly need to do studies such as this in children, but it is possible that this will give a negative result even if the drug is effective and durable, and that might be able to be shown before this is completed or even started.

DR. GULICK: Could we ask the sponsor, the sample size and what power of a difference in virologic response that the study is looking for? I am sorry, it says n equals 100. What kind of difference are you powered to detect?

DR. TOOLE: DAVG, 0.5 difference between tenofovir and placebo.

DR. GULICK: 0.5 logs?

DR. TOOLE: 0.5 logs.

DR. GULICK: Over 48 weeks.

DR. TOOLE: Over 40 weeks. We are also considering either changing the DAVG40 as the second endpoint to time to failure, as well.

DR. WONG: I guess maybe my real question is to the Agency, how do they interpret the results in the sponsor's Slide 22 with respect to durability of antiviral effect of tenofovir?

DR. STRUBLE: I think we overall fundamentally agree with the results, but however, after week 24, there are a lot of treatments switches that happened on the tenofovir arms.

So, although it appears that it is a durable response, we have to take a closer look to make sure that response wasn't attributed to the addition of new drugs over the last 24 weeks.

DR. WONG: If you were to decide that that was not the explanation and the naive study that is currently underway should show an effect, then, it would seem to me that the major burdens are met, right, no matter what this study shows.

DR. STRUBLE: I think we looked at all the data in the entirety with the evidence from the 902, the results of this study, the naive study. We look at the data as a whole to make the determination for traditional approval, and I think all that information will help.

DR. GULICK: Dr. Englund.

DR. ENGLUND: Just a couple comments about the pediatric study. First of all, I am wondering why there is a two-week--and I wasn't involved in this--why there is just a two-week addition of the single drug, because one of the concerns I have is if you do optimize everyone's regimen as was said, you may optimize everyone's regimen with or without the tenofovir.

If you expanded the first initial two-week introductory period, you went to, I don't know, four weeks or eight weeks, you would actually mimic what you have done in the adult trial, and you would at least get some baseline data to show that, as a single agent, that it works, and you could get more virology data, you could get more points in time to actually look at the resistance, and that is one suggestion.

The second one is agreeing with Dr. Yogev. I think it needs to be stratified at the very least into younger children and older children because there is a big difference between two-year-olds and 12-year-olds, but I mean two to six, maybe we could put together, but certainly you get over the age of six, and there is a lot of difference in just PK studies and disposition of drug.

DR. GULICK: Just by way of background, the committee actually spent a whole session on the design of salvage therapy studies. We had a lot of debate about the point that you raised, how much of an initial period do you want one drug versus placebo to try to assess antiretroviral activity.

There were a number of opinions about that. Two weeks was one option in terms of bouncing risks and benefits. It may not be the only way to do it certainly.

Dr. Sun.

DR. SUN: Just an observation and a question. Why should this study be restricted to people that have failed all three classes of drugs? If you look at the overall clinical data that you have at the end of the day, 902 and 907 are in heavily experienced patients. 903 is going to be in naive patients, and there is plenty of patients who are experienced with one or two classes. It seems like that might be an opportunity to do a clinical trial.

DR. STRUBLE: So, you are saying in patients that only have experience with one or two classes?

DR. SUN: One or two classes.

DR. STRUBLE: As a possibility?

DR. SUN: Right. Just to have a broader patient population exposed to the drug.

DR. GULICK: You said two different things, and we should be clear about it. You said experienced with all three classes, and then you said failed all three classes. Clearly, there is a difference between those.

This says experienced as currently written, so your point applies, but just to make that distinction for the committee.

Dr. Schapiro.

DR. SCHAPIRO: Just to address both the comments of Dr. Wong and Dr. Sun. There is a tradeoff here. We assume that the optimizing will not bring the patients undetectable, and therefore it does matter a little bit.

I think we have to design this feeling that there will be a delta between adding our new drug on the optimized background versus the optimized background, so we do have to have a sick enough patient population that there will not be, in the majority of them, undetectable viral load with optimization.

That is why this was part of that very elaborate discussion we had. The tradeoff with the two, four, and eight weeks that were discussed is, on the one hand, as you said, the longer we go, the more data we have, but, of course, we don't want patients who develop mutations by having effective monotherapy in a way.

Here, for example, we believe that if you optimize background, you might prevent, let's say, the K65R, the longer we go without that, we would have a greater--so, these are the tradeoffs, and we did have a whole session on it, but I think these were some of the things that we had discussed, and I think that is sort of how we came to two weeks as one option.

DR. GULICK: Dr. Stanley.

DR. STANLEY: But again, in this particular case, we now have data from the 902 and 907, where adding it on, they didn't high level of resistance. There was the 3 percent that developed, but I am just saying with this particular--that was a concern why we settled on two weeks previously, because we were afraid of adding a drug and getting rapid development of resistance.

There is at least some data here that would suggest that that is not a tremendous upswing, but does that apply to children, I don't know.

DR. GULICK: Does that apply to all levels of viral load?

DR. STANLEY: Right, and to the 30,000 viral load.

DR. SCHAPIRO: Here, you are generating more, I mean we have 30,000, so I think there is a danger of that.

DR. GULICK: Dr. Yogev.

DR. YOGEV: Just for the sake of the kids, I don't think we should ask the company to take more blood, viral load, in the first two weeks. It is a very interesting issue, but multiple studies show that you get to a certain point, and that's it.

This is a clinical study, so if you want to do a subgroup I won't argue. As for the old classes, many of our patients will be on two classes that will open it really to enroll many more patients because our next step will be for three, so those will be more expense than experience can be, and that becomes a salvage protocol, and it would be interesting for the experience to be in it.

So, I would suggest go to two classes, and as for the n, the combination, correct me, but I thought they mentioned 100 patients. I don't think with this type of study, 100 would be sufficient, and they need to work it out to get the right number.

Why are we stopping in 48 weeks if it is working? Why shouldn't the study go to 96 and above? One of the major problems is when you stop what you are doing, so I think as long as we see that there are data, and we have a question on toxicity, whatever longer, especially this population, I highly recommend to go to longer period of the study, not necessarily to get approval from the FDA.

DR. GULICK: Can we ask the sponsor just in follow up to that, would there be plans to extend or have a rollover study for the children in this study?

DR. TOOLE: [Off mike.]

DR. GULICK: So, the answer was that they would have continued access to tenofovir.

DR. YOGEV: I was not afraid of access because immediate they proved it out, we have an access. We were surprised to find out the drug like ritonavir, the toxicity in several of our patients appeared very foreign to the study, which were not known to the adult, and I am just trying to raise the issue of safety.

DR. GULICK: So, you are visiting an issue that we visited earlier today, which is to say we need longer term safety, not just in adults, but pediatrics, too.

Dr. Struble.

DR. STRUBLE: I would just like to bring up with the treatment experience, I think one of the reasons why it is treatment-experienced with all three drug classes is because of the bone toxicity issue in children, is that I think that the risk may be different in children, and I think that we are choosing a patient population that will accept a little more risk versus choosing a patient population that may be experienced with one or two drug classes.

I think what they propose is a reasonable approach at this time until we fully understand the true mechanism and have some additional long-term safety.

DR. YOGEV: If you do that, just be prepared, you are going to have very few kids less than two years of age who are going to be on three classes.

DR. STRUBLE: We realize that.

DR. YOGEV: Unfortunately, you get what happened was more than we would like to see in pediatrics. The drug was approved for much lower age group.

DR. STRUBLE: We are going to be getting that from pharmacokinetic studies, stratifying by age. We will get some pharmacokinetics in younger children that might not necessarily fit into this, and some long-term safety.

DR. YOGEV: But those are short studies. As long as they go long in high number, because I think the bone is very rare, and you might find it, but--

DR. STRUBLE: One of the PK studies is a 48-week study.

DR. GULICK: Let's come to some conclusions about this. The consensus of the committee is that we like this design, it was one of the ones that we actually came up with at our salvage session last year, so we are supportive.

We talked about the tradeoffs of doing two weeks in terms of ability to detect a difference depending on viral load level, the risk of mutations, the risk or prior experience, some debate about whether two versus three drugs is appropriate, and then assessing risk versus benefit in those patients particularly with toxicity in mind.

Dr. Wong raised the point what if no difference is detected here, and the answer from the Agency's point of view was really we need to consider this in the context of all the studies.

There were some concerns about stratification based on ages from a couple of our pediatricians, also PK and safety issues, and finally, that the first two weeks is the critical part of this study, so that the number of samples should be appropriate to really detect a difference.

In the last remaining minutes, let's consider as a group other studies that we would like to see, and particularly the Phase IV commitments that we would suggest to tackle some of the issue we have been considering all day.

Dr. Munk jumping in.

DR. MUNK: Jumping in. With the Chair's indulgence, slightly off topic.

DR. GULICK: Ooh.

DR. MUNK: This is a request to the sponsor, as well as to the Agency. I am assuming that tenofovir will be indicated to be taken with food, and my request is that in all the documentation that we have received, there are references to a high fat meal, a standardized high fat meal, and the request is that in any case where there is a food indication or requirement, that the terms meal, high fat meal, snack be translated in patient-oriented materials into very concrete lists of food.

Does a high fat meal mean a Big Mac and fries, or a cheeseburger with a milkshake? And that is really literally the level of detail that I think is needed in food lists. I can't tell you how many inquiries I have gotten about what does a snack mean, what does a light meal mean, and so just providing kilocalories and percent calories from fat is not enough.

DR. STRUBLE: We hear this comment quite often from patients actually receiving the products. You know, a high fat meal, our Clin Pharm people can comment actually more, but there is a standardized meal that they take to do these studies, but the clinical trials were done, patients were instructed to take tenofovir with a meal, and that is what the proposed wording is. There was no set meal that people had to take.

DR. MUNK: I guess, then, just a footnote would be if that is the case, then, that needs to be communicated to patients that the patients were simply instructed to take it with a meal, and that that is what all these clinical results were based on.

DR. STRUBLE: That is a very good point, thank you.

DR. GULICK: Let's shift gears back to Phase IV commitments. Dr. Schapiro.

DR. SCHAPIRO: Dr. Fletcher isn't here with us today, so I think drug interactions are underrepresented, but I do think that if he were here, we would be hearing that we definitely have to do the studies and that you can predict them.

I think that the possible interaction with Kaletra would not be expected with what we know from people. I think we do have to do those studies. I think that is actually something which we really, really need to have interactions. They don't take long, but I think those need to be done.

I also think honestly, we saw very little data actually looking at the appropriate dose. I think the 600 dose was started with actually four experienced patients, a total of versus eight patients. There was very little data.

I would be cautious to just go forward. We have seen with other drugs that the community may react in a way that they have done with other drugs, that if there is not a good answer, then, we get a lot of experimentation being done, and if this drug may have toxicity that is dose related, it might be better that that be done in an organized way, and not that we find ourselves like the PIs now, having everyone use a different one, so those would be two that I would suggest.

DR. GULICK: Do you want us to get more specific about drug interactions?

DR. STRUBLE: I was just going to ask Dr. Schapiro that question. What specific drug interactions would you like to see?

DR. SCHAPIRO: The first one that comes to mind, which I was concerned about, was the ritonavir.

DR. STRUBLE: With different doses of ritonavir?

DR. SCHAPIRO: Well, Kaletra is 133 mg of ritonavir, and that actually had a significant increase in tenofovir. If that is linear, then, a dose which is very commonly used in the patients who will be receiving that drug, the minute we approve it, will be patients who get 400, which could give a much higher interaction, and some of the toxicities, which we are worried about, we have no data on what happens if you have twice the levels.

The first one I would jump into, I think also, I don't know for the NRTIs what was done, if they were covered, but I think the first one I would do right away would be 400 mg of ritonavir to start with, and I would probably look at the other NRTIs, as well.

DR. STRUBLE: Sustiva was done, 3TC was done, ddI with the old formulation was done. They are going to go back and do the enteric coated, because there was an interaction with ddI with the buffered formula.

DR. SCHAPIRO: And nevirapine?

DR. STRUBLE: Sustiva was done. Nevirapine, I don't believe was done, no.

DR. GULICK: So, would you suggest nevirapine?

DR. SCHAPIRO: I am a little bit lost, but I think that is an important thing to be done, because we are going to be combining that as soon as it comes out.

DR. GULICK: Dr. Yogev.

DR. YOGEV: I think you mentioned before saquinavir as an issue that was not resolved, which I think should go, and to my surprise, nelfinavir, which many of my colleagues is drug number one in the PI. I couldn't find any data, but I would go to a different interaction that might be of importance is drugs which are excreted by the kidney, that might have an effect.

DR. STRUBLE: Those are planned, too.

DR. YOGEV: Aminoglycosides, probenecid, this type of drug which have an effect, might have a cumulative effect. As for study, just because I didn't mention before, I would like to see them going less than six months of age in the pediatric, and I was negatively impressed, as Dr. Kumar was, about how few women are there, and I think we see more and more data that women are not--so, we need data on women studies for them, and work on them.

One other interesting point, I was impressed that in dendritic cells, supposedly the drug was the most active, and this is the beginning of the infection. That is what we are believing now, that it start with dendritic cells, and the long half-life suggested this drug. AZT, by itself, is not as active as tenofovir by itself. It is a monotherapy.

So, one other study which might be considered is a perinatal study for transmission, that might be because of the lack of toxicity, and more important is the lack of development of resistance. Nevirapine is already running into trouble because so quickly resistance was found.

AZT, we are seeing more and more now transmitted or resistant. Here is a drug that is very difficult to develop resistance, it looks like, and have all the positivity that might have a very good impact on this type of study that I would love to see.

DR. GULICK: Dr. Johnson.

DR. JOHNSON: At least in our clinic, a lot of HIV HCV coinfected patients are needing interferon alpha, ribivirin, and ribivirin is renally excreted, and that gets to be a question, especially is they are on 3TC and now you are going to put them on tenofovir.

DR. GULICK: Dr. Englund.

DR. ENGLUND: I think that a big population for this drug is going to be those patients who are failing all kinds of therapy, and we really need to assess Bactrim and Azithro. Those patient are on routinely the day it is licensed, they are going to be on those, and we don't know any of the interactions. That was number one.

Number two, I am concerned about hepatitis B, those of our patients that do have high levels, and I think I would encourage the company to at least be evaluating what is going on with the hepatitis B genotyping and quantitation in patients that are on study. I think that that is a matter of interest, and you wouldn't want to ignore that.

Number three, I think we need to also really access this drug in the studies to women of color and minority women, which is where the outbreak is affecting them the most, and women are underrepresented in these trials, but certainly our minority women are heavily underrepresented.

DR. GULICK: Dr. Johnson, a follow up?

DR. JOHNSON: Yes, just on the comment, too, and support of Gilead, has worked closely with the adult ACTG, protocol A5127, that will compare tenofovir versus adefovir for treatment of coinfected HIV HBV infected patients failing 3TC to get to one of the community comments earlier. There will be intensive HIV and HBV resistance longitudinal analysis planned in that study.

DR. GULICK: Dr. Tebas and then Dr. Hamilton.

DR. TEBAS: As a clinician, if it works well in 903, I would like to see studies looking at one of the combinations, because I think it is probably where it is going to be used in the future, and another area that I think potentially has a good market is for post-exposure prophylaxis. The tolerability of the drugs that we use versus post-exposure prophylaxis like nelfinavir is poor. I realize that it is going to be very difficult to show efficacy, but if this drug is a part of the nucleoside regimen, it is better tolerated. It looks like it is not very toxic and is for a short period of time, and most people stop immediately afterwards, that might be potentially an indication for this drug, if it is better tolerated than the currently off-label drugs.

Almost half of the people that start post-exposure prophylaxis in the hospital, they stop the drugs because of side effects, and this could be potentially a place that it can be used.

DR. GULICK: Dr. Hamilton and then Dr. Munk.

DR. HAMILTON: Given the sponsor's intention to rollover 901, 902, and 907 into 910, with the proposed follow up of up to four years, I would encourage them to collect clinical endpoints for later analysis relative to whatever has gone on with respect to surrogate markers, resistance, whatever.

In addition, the appearance within the last month of these provocative reports in the New England Journal that indicate GB virus C having an effect on longevity, is bothersome at the very least, but may be an opportunity to look at, if that is real, whether there may be some earlier confounding effect.

DR. GULICK: Dr. Munk.

DR. MUNK: Yes. Could I ask the sponsor just to remind me, in 903, what is the baseline viral load?

DR. TOOLE: The mean baseline viral load in 903 is around 75,000.

DR. MUNK: Is it stratified at any point by viral load? It is stratified at over and under 100,000? Thank you.

DR. GULICK: Other comments from the committee?

Let's summarize this point. We have really been thinking about Phase IV commitments all day with some of the issues that we have covered. The committee is in agreement that long-term safety is critical here, both for bone, renal, and other potential toxicities.

Measures of efficacy, particularly the CD4 responses, given some of the conflicting information we saw today, mutations, that is resistance, mutations over time, and Dr. Hamilton threw in at the last minute clinical endpoints are worth assessing in a four-year long clinical study.

We have a number of other populations that we would like to see data in - children less than six months of age. Many times the point was made that in the initial studies, women were underrepresented, particularly women of color on those studies.

Other groups that were suggested over the course of the day, those with baseline renal insufficiency, those with baseline hepatic insufficiency, those with concomitant, either hepatitis B infection because of the drug's activity against hepatitis B, and/or hepatitis C activity, either treated or not treated. Those with baseline bone disease or those who developed bone disease from other HIV drugs or the disease itself.

Other potential groups to look at, pregnant women, the setting of perinatal transmission, the setting of post-exposure prophylaxis, and the once-a-day setting or perhaps even DOT with antiretrovirals.

How is that for a short list to look at?

Drug interactions was one area that the committee felt pretty strongly about, even though Dr. Fletcher isn't here, and we will tell him that he was remembered fondly.

Some of the drugs that we felt important in terms of antiretrovirals, nevirapine, in terms of the protease inhibitors ritonavir at a dose of at least 400, saquinavir, nelfinavir were all pointed out. Importantly, OI prophylaxes, which will be commonly used in this population, Bactrim and azithromycin being two of the more common, and then renally excreted drugs, such as the aminoglycosides and probenecid.

There was some question about dose selection based on the early Phase I studies.

I think that is it. From the Agency?

DR. STRUBLE: I would like to thank everyone for their comments. I think we got a lot of useful information to help us write an indication in the micro section of the label. We appreciate that.

DR. GULICK: I would like to take this opportunity to thank the committee for a very thoughtful and patient day. I would like to thank the sponsor for grace under fire or under rain, as we say, thank the Agency for allowing the day to go so smoothly, and thanks to the audience, too.

[Whereupon, at 4:58 p.m., the proceedings adjourned.]

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