# Presentation: 681013

## Tenofovir Disoproxil Fumarate

**NDA  21-356**
**October 3, 2001**
**Gilead Sciences, Inc.**
**Foster City, CA**

**Notes:**
Good morning.
My name is Norbert Bischofberger from Gilead Sciences.
We are here to review the New Drug Application for TDF, which was submitted to the FDA on May 1, 2001.

## Gilead Consultants

**Harry K. Genant, M.D.**
- Professor of Radiology, Orthopedic Surgery and Medicine
- University of California, San Francisco
**Robert T. Schooley, M.D.**
- Chair, Adult AIDS Clinical Trials Group (AACTG) Executive Committee
- Head, Division of Infectious Diseases, and Tim Gill Professor of Medicine
- University of Colorado Health Sciences Center
**Steven L. Teitelbaum, M.D.**
- Wilma and Roswell Messing Professor of Pathology and Immunology
- Washington University, St. Louis

**Notes:**
Joining us today are the following Consultants:

## Tenofovir Disoproxil Fumarate (TDF)

**Overview of Development Program****	****	****         ****Norbert Bischofberger, Ph.D.****	****	****	****	****	****	****	**
- Clinical Trial Results                              		  Jay Toole, M.D., Ph.D.
- Concluding Remarks                                           Norbert Bischofberger, Ph.D.

**Notes:**
In today’s presentation I will review the TDF preclinical data and the clinical development program.

Dr. Jay Toole will present the efficacy and virology data from our clinical studies and I will end our presentation with concluding remarks.

Despite the number of antiretrovirals available today, there is still a tremendous unmet medical need.  People with AIDS and their caregivers face daunting challenges with resistance, compliance, drug interactions, tolerability and durability of treatment effect.

Tenofovir disoproxil fumarate is a novel antiretroviral which address of these challenges.

## Tenofovir Disoproxil Fumarate (TDF)

- Orally bioavailable prodrug of tenofovir (PMPA)
- Nucleotide RTI
- One tablet, once daily
- Durable activity against nucleoside resistant HIV

**Notes:**
Tenofovir Disoproxil Fumarate is an orally bioavailable prodrug of TDF.

Tenofovir contains a phosphonate, it is an analog of AMP and is therefore a nucleotide reverse transcriptase inhibitor.

Tenofovir is given as one pill, once daily and it has a unique resistance profile showing durable activity against otherwise nucleoside resistant viruses.

The unique resistance profile of tenofovir is evident from cross resistance studies.

## In Vitro Virology

- Active *in vitro *against recombinant HIV with
- ZDV resistance (D67N, K70R or T215Y)
- ddl resistance (L74V)
- ddC resistance (T69D)
- multinucleoside drug resistance (Q151M complex)
- Increased activity against HIV with 3TC resistance (M184V)
- Can select *in vitro* for the K65R mutation in RT
- 3- to 4-fold reduced *in vitro* susceptibility to tenofovir

**Notes:**
In vitro TDF retained activity against viruses expressing TAMs with ZDV resistance against viruses expressing L74V ddI, the resistance mutation, the T69D ddC resistance mutation and the Q151M multinucleoside resistance mutation.

It shows increased activity against HIV expressing M184V, the 3TC resistance mutation.

In in vitro selection experiments, virus containing the K65R mutation emerged exhibiting 3-4 fold reduced susceptibility.

The resistance profile was confirmed when TDF was evaluated against a number of clinical HIV isolates.

## Susceptibility of Nucleoside-ResistantHIV-1 Clinical Isolates (Virco)

**0.7**

**0.6**

**0.7**

**1.7**

**0.1**

**1.0**

**10.0**

**100**

**3.0**

**2.5**

**M184V****(n=10)**

**L74V****(n=5)**

**L74V + Y115F + M184V****(n=5)**

**Q151M****Complex****(n=10)**

**K65R****(n=8)**

**T69 ****Insertions****(n=15)**

**Fold Change from Wild-Type**

**11.7**

**Normal Range (**_**<**_** 3-fold)**

**Resistant (> 10-fold)**

**Intermediate Susceptibility (3-10-fold)**

**T215Y +****other ****TAMs****(n=20)**

**3.1**

**Notes:**
3TC resistant viruses expressing the M184V, ddI resistant viruses expressing L74V and abacavir resistant viruses expressing L74V, Y1115F, M184V were hypersusceptible to TDF with a mean 0.6 to 0.7 fold change from WT. Multinucleoside resistant viruses expressing the Q151M complex or viruses expressing K65R fell in general within the normal susceptibility range, <3 fold change from WT.

High level ZDV resistant viruses containing the T215Y along with other TAM mutations, showed WT susceptibility, within 3 fold change, or intermediate susceptibility 3 to 10 fold change from WT.  

The only mutation resulting in hi level resistance to tenofovir is the uncommon T69 insertion, causing a mean 12 fold decrease in susceptibility.

## Pharmacology

- Once-daily dosing
- Long intracellular half-life (10-50 hours)
- Terminal serum t1⁄2 ~17 hours
- Not a substrate, inhibitor or inducer of CYP450
- No clinically significant drug interactions with EFV, IDV, LPV/RTV (Study 909)
- Renally cleared
- Clearance not affected with co-administration of 3TC or ddI  (Study 909)
- Oral Bioavailability:  25% (fasted); 39% (fed)

**Notes:**
TDF is dosed as one pill once daily.  Once daily dosing is supported by the long intracellular half life of TDF in human PBMC’s ranging from 15 h in activated cells to >50 hr in resting cells and by the pharmacokinetic terminal serum t1/2 which is ~16hrs in humans..

Tenofovir does not exhibit any clinically significant drug interactions.  This was shown in study 916 which evaluated pharmacokinetic during interactions of TDF with the NNRTI EFV, with the PIs IDV, LPV/RTV and the nucleosides 3TC and ddI.  The lack of drug interactions with compounds which interact with the P45o system is consistent with the finding that in vitro, TDF is not a substrate, inhibitor or inducer of P450 interaction studies in pharmacokinetic drug with EFV, IDV, LPV/RTN and the nucleosides to 3TC and ddI.

## Preclinical Toxicology

- No effect on mitochondrial DNA or lactate production *in vitro*
*In vivo* studies designed to identify potential target organs in humans:
- GI
- Kidney
- Proximal tubular changes
- Bone
- Osteomalacia associated with nephrotoxicity in juvenile monkeys at 12x human AUC
- Reversible
- No radiographic evidence of bone changes in monkeys dosed at 4x human AUC for 3 years

**Notes:**
Data obtained from enzyme inhibition experiments and cell culture in vitro suggest that TDF has a low potential for mitochondiral toxicity.
In vivo toxicology studies in animals which are designed to identify potential target organs in humans indicated GI, kidney and bone as target organs.
Toxicity to the GI is a local high dose effect observed only in rats which were administered 1000 mg/Kg TDF to overcome the low oral bioavailability in that species.
Nephrotoxicity was seen in dogs and monkeys and was characterized by proximal tubular changes
Bone effects were seen in rats, dogs and monkeys.
When a lower dose of TDF was used resulting in 4x human exposure, there was no radiographic evidence of bone changes even when TDF was dosed for 3 years.
With the identification of kidney and bone as potential target organs, we instituted appropriate monitoring in our clinical studies.  As you will hear in Dr. Tool’s presentation, there is no evidence of TDF related nephrotoxicity or bone toxicity in humans.
The safety data base in our NDA consisted if the most significant effects on bone were observed in juvenile monkeys which were dosed subcutaneously with tenofovir at ~12x human exposure.  These animals developed nephrotoxicity and bone effects characterized as osteomalacia.
Osteomalacia was reversible on drug discontinuation or dose reduction.

## NDA Safety Database

- 									    **Patients receiving 300 mg*****a***
- 										**Total****	****      ****	****  ******** ****48 weeks ****	**
- NDA Submission			 	 978				   154
- (May 1, 2001)
- NDA Safety Update		    		 978				   642
- (August 15, 2001)
***a ***Includes placebo-controlled studies and compassionate access (Study 908)

**Notes:**
Close to 1000 HIV infected patients who received TDF 300 mg.  At the time of the NDA submission which was May 1, 2001, 185 of these had received TDF for at least 48 wks and at the time of the safety update, which was August 15, 2001, a total of 792 patients had received TDF 300 mg for at least 48 weeks.

## Tenofovir Disoproxil Fumarate (TDF)

- Overview of Development Program		         Norbert Bischofberger, Ph.D.	**	****	****	****	****	****	**
**Clinical Trial Results                              ****	**** ****Jay Toole, M.D., Ph.D.**
- Concluding Remarks                                     Norbert Bischofberger, Ph.D.

**Notes:**
With that I would like to ask Dr. Toole to present the efficacy, safety and virology results from our clinical studies.

Good morning, my name is Jay Toole and I will be presenting the clinical trial results of tenofovir.

We conducted 3 placebo-controlled studies:

## Overview

- Placebo-controlled Studies
**	****	****Design****	****Dose (qd)**
- Study  901	Monotherapy (n=49)	75,150, 300 & 600 mg
- Study  902	Intensification (n=186)	75,150 & 300 mg
- Study  907	Intensification (n=550)	300 mg
- Renal and Bone Parameters
- Clinical Virology

**Notes:**
Study 901 evaluated tenofovir as short-term monotherapy at 4 dose levels.

Studies 902 and 907 were longer duration, intensification studies in which tenofovir was added to stable background regimens.

The intensification design was chosen as we believe it allows the clearest demonstration of the impact of a single agent in combination regimens as compared to a fixed 4 versus 3 drug regimen. 	

Study 902 evaluated 3 dose levels, and 907, our phase 3 study evaluated, tenofovir 300 mg the dose for which we are seeking approval

In addition, I’ll present data on renal and bone parameters and from our clinical virology studies. 

## Study 901Design

- Randomized, double-blind, placebo-controlled, dose-escalation study of TDF monotherapy
- 4 dose levels (75 mg, 150 mg, 300 mg, 600 mg/day)
- HIV RNA ****** **10,000 copies/mL; CD4 ****** **200 cells/mm3
- 10 patients per dose level (8 TDF, 2 placebo)
- Single dose (day 1) followed by one week washout, then once-daily dosing (days 8 to 35)
- Treatment-naïve and experienced patients were enrolled

**Notes:**
We began with study 901, a randomized, double-blind, placebo-controlled dose escalation study of tenofovir monotherapy.

To enroll patients had HIV RNA >10,000 and CD4 count > 200.

Four doses were studied, ranging from 75 to 600 mg.

There were approximately 10 patients per dose level, 8 active, 2 placebo.

Patients received a single dose on day one for pharmacokenitic sampling, then after one week, 28 consecutive days of dosing.

Both treatment naïve and experienced patients were included, with the following baseline characteristics.

## Study 901Baseline HIV Characteristics

- 	**Placebo **	**TDF****	**** ****	****(n=11)****	****(n=38)****	**
- Mean CD4 (cells/mm3)	346 	391
- Mean HIV RNA (copies/mL)	115,593	85,351
- Prior ART use**	**36%	68%

**Notes:**
Mean CD4 counts of 346 and 391 and, mean HIV RNA of about 85,000 and115,000.

 68% of the active group had prior antiretroviral experience, compared to about 36 of placebo.

Significant activity was observed.

## Study 901HIV RNA

**Placebo****	****75 mg****	****150 mg****	****300 mg****	****600 mg**
**  ****(n=9)****	****(n=10)****	****  (n=8)****	**** (n=6)****	****  (n=8)**
-    0.03	-0.33*****	  -0.51*****	  -1.20*****	  -0.84*****

*******p<0.003**

- Mean Change from Baseline to Day 35 (log10 c/mL)
- As Treated

**Notes:**
For the mean change in HIV RNA from baseline to day 35, there was little change in the placebo arm, and a dose response was observed with maximal activity at 300 mg which showed a 1.2 log decrease.

Each dose group was significantly different compared to placebo, with p-value <0.0003 .

After day 35, dosing was dlc

## Study 901Mean Change from Baseline in HIV-1 RNA

- Intent to Treat

**Notes:**
and there was a slow return of viral load to baseline  one week after dosing the 300 mg and 600 mg groups still remain about one-half log below baseline, consistent with the long intracellular half-life of the active moiety.

To confirm the efficacy in a larger number of patients, and to examine long term safety at three dose levels, we conducted Study 902,

## Study 902Design

- Randomized, double-blind placebo-controlled study of TDF added to existing antiretroviral regimens
- Entry criteria:
- Stable ART  8 weeks prior to entry consisting of  4 concomitant antiretroviral agents
-  HIV RNA  400 - 100,000 copies/mL
- Primary Efficacy Endpoint
- Time-weighted average change from baseline in HIV RNA (log10 copies/mL) at week 24 (DAVG24)

**Notes:**
which was a randomized, double-blind placebo controlled study.
Patients must have received a stable background regimen of up to 4 approved drugs for at least 8 weeks and have HIV RNA between 400 and 100,000 copies/mL.
The primary efficacy endpoint was the time-weighted average change from baseline in HIV RNA at week 24, called DAVG24.
This endpoint, which was also the primary endpoint in Study 907, was prospectively discussed with and agreed to by the agency.

## Study 902Design

**Stable ART**
****** ****8 weeks **
**randomized**
**2:2:2:1**

**24 wks**

**48 wks**

**75 mg**

**75 mg**

**300 mg**

**150 mg**

**150 mg**

**300 mg**

**300 mg**

**300 mg**

**300 mg**

**Placebo**

**300 mg**

**300 mg**

**Open Label**

**Double-blind**

**n=186**

**Notes:**
Patients were randomized to either one of 3 doses of tenofovir or placebo, in a 2:2:2:1 ratio.
The double-blind phase was 48 weeks.  
After 24 weeks patients on the placebo arm rolled over to tenofovir 300mg in blinded fashion for the next 24 weeks.
After 48 weeks, patients received the 300 mg tenofovir dose for an indefinite period in the open-label phase,
186 patients enrolled and received drug.

## Study 902 Baseline HIV Characteristics

- Mean CD4 (cells/mm3)          	374
- Median HIV RNA (copies/mL)  	5010
- Mean prior ART (years)	4.6
- Baseline resistance
- NNRTI	32%
- PI		57%
- NRTI	94%

- (n=186)

**Notes:**
Their overall baseline characteristics show a mean CD4 count of around 370 and, a viral load of around 16,000.

Patients were highly treatment-experienced with mean antiretroviral use of over 4 1/2 years.

Baseline genotyping was performed and identified primary resistance mutations associated with non-nucleosides in 32% of patients, protease inhibitors in 57% , and nucleosides in 94% of patients.

Tenofovir was well tolerated.

## Study 902Patient Disposition

**	****	****	****	****                  ****TDF**
**	****	****Placebo****	****75 mg****	****150 mg****	****300 mg**
- Patients who received drug 		28		 53		  51		 54
- Patients discontinued (%) 	7 (25%) 	5 (9%) 	8 (16%) 	6 (11%)
- Adverse events	1 	  (4%)	2 (4%)	5 (10%)	2   (4%)
- Lost to follow up	2   (7%) 	1 (2%)	2   (4%) 	1   (2%)
- Lack of virologic response	2   (7%)	0	0	0
- Death	0		1 (2%)	0	0
- Other	2   (7%)	1 (2%)	1   (2%)	3   (6%)

- (0-24 weeks)

**Notes:**
With the highest percentage of discontinuations in the placebo group, at 25%, compared to 9-16% in the three active dose groups.

4% of patients discontinued due to an adverse event in the placebo group, with 4 to 10% in tenofovir  groups.

There was one death in the study, a suicide which occurred in the 75mg treatment group and was not attributed to tenofovir by the investigator.

## Study 902Patient Disposition

**	****	**** ****	****                       ****TDF**
** ****	****	****	****  ****75 mg ****	****150 mg ****	**** 300 mg**
- Patients who received drug		    53	   51	    54
- Patients discontinued (%)		14 (26%)	12 (24%)		13 (24%)
- Adverse events		  6 (11%)	  5 (10%)	    5   (9%)
- Lost to follow up		  3   (6%)	  5 (10%) 	    3   (6%)
- Lack of virologic response	     2   (4%)	  0		  0
- Death		  1   (2%) 	  0		  0
- Other 		  2   (4%)	  2   (4%)	    5   (9%)

- (0-48 weeks)

**Notes:**
Through 48 weeks the percentage of patients who discontinued increased to about 25% in the three dose groups.

Importantly, the percentage of patients who discontinued due to adverse events remained low at approximately 10%, and was similar in each dose group.

The primary efficacy endpoint demonstrated activity

## Study 902Primary Efficacy Endpoint

- 		**	****  ****TDF**
**	****Placebo****	****75 mg****	****150 mg****	****300 mg**
-   Intent to Treat	 +0.02	-0.26	  -0.34	  -0.58*
-   As Treated	 +0.16	-0.16	  -0.32*	  -0.52*

***p<0.001**

- Mean DAVG24 (log10 copies/mL)

**Notes:**
Mean DAVG24, with the 300 mg dose group showing a 0.58 log reduction compared to 0.02 increase for placebo; this was highly statistically significant.

Approximately 30% of the patients in each treatment arm changed their background antiretroviral regimen during the first 24 weeks.

To preclude the possible effect of this, we also determined the DAVG24 for the As-Treated population, for whom data were excluded after changing background therapy or discontinuing study.

The response in the 300 mg group is similar for the As-Treated and Intent-To-Treat populations, and remained statistically significant.

The changes at week 24 were durable.

## Study 902Mean Change from Baseline in HIV-1 RNA

- Intent to Treat

**Notes:**
The mean HIV RNA changes from baseline, showing a decrease of -0.6 logs in the 300 mg group at week 24, which was maintained out through week 48

## Study 902CD4 Count

- 					  	   **TDF****	****	**
**	****Placebo****	****75 mg****	****150 mg****	****300 mg**
**	**** ****(n=28)****	****(n=53)****	**** (n=51)****	**** (n=54)**
- Week 24		20		18	 	  0			-14
- Week 48	   N/A		10		20			 11

- Mean Change From Baseline (cells/mm3)
- Intent to Treat

**Notes:**
The changes in mean CD4 counts at week 24 were not significantly different between the active and placebo groups, and the changes remained modest at week 48.

The safety profile was favorable

## Study 902Grade 3/4 Adverse Eventsa

-  **	****	****     ****	****	****  ****	****    ****TDF**
**	****	****Placebo****	****   75 mg ****	**** 150 mg****	****300 mg**
**	****  ****	****(n=28)****	****  (n=53)****	**** (n=51) ****	**** (n=54)**
- Patients (%) with Events	4 (14%)	10 (19%)	9 (18%)	9 (17%)
- 	Depression	0	 	 2 (4%)	0	3 (6%)
- 	Asthenia	1 (4%)	 0	2 (4%)	0
- 	Hepatitis	1 (4%)		1 (2%)	0	0
- 	Fever	1 (4%)		1 (2%)	0	0
- 	Headache	1 (4%)		0	1 (2%)	0
- 	Pancreatitis	1 (4%)		0	0	1 (2%)
- 	Allergic reaction	0			0	0	2 (4%)
- 	Pain	0		  1 (2%)	1 (2%)	0

***a***** ********1% in either group**

- (0-24 weeks)

**Notes:**
The percentage of patients with grade 3 or higher adverse events was 14% in the placebo, and ranged from 17 - 19% in the active groups.

The adverse events which occurred in > 1% of patients shows the incidence of events is generally similar between the active and placebo group.

Grade 3 or 4 adverse events from 0-48 weeks show no change in the profile, and no event appeared dose-related.

## Study 902Grade 3/4 Laboratory Abnormalitiesa

- 		 **Placebo****	****   75 mg****	**** 150 mg****	**** 300 mg**
**	****  ****	****  ****(n=28)****	****   (n=53)****	****  (n=51)****	**** (n=54**)
- Patients (%) with Abnormality**	**** **9 (32%)	18 (34%)	16 (31%)	16 (30%)
- 	Triglyceride elevation**	**** **4 (14%)	  9 (17%)	  4   (8%)	  5   (9%)
- 	Creatine kinase elevation	 4 (14%)	  5   (9%)	  4   (8%)	  6 (11%)
- 	AST elevation	 1   (4%)	  3   (6%)	  3   (6%)	  4   (7%)
- 	Neutropenia	 1   (4%)	  3   (6%)	  1   (2%)	  3   (6%)
- 	ALT elevation	 1   (4%)	  2   (4%)	  2   (4%)	  1   (2%)
- 	Lipase elevation	 1   (4%)	  1   (2%)	  2   (4%)	  1   (2%)
- 	Amylase elevation 	 1   (4%)	  2   (4%)	  2   (4%)	  0
- 	Hyperglycemia	 0	 	  3   (6%)	  2   (4%)	  0
- 	Glucosuria	 0	  	  2   (4%)	  1   (2%)	  0
- 	Bilirubin elevation	 0	 	  1   (2%)	  1   (2%)	  1   (2%)
- 	Thrombocytopenia	 0 	  0		  2   (4%)	  0

- Study 902**Grade 3/4 Laboratory Abnormalities***a*

***a********* 1% in any group**

- (0 - 24 weeks)

**Notes:**
Grade 3 or higher laboratory abnormalities were more common, occurring in 32% in the placebo group, and in the active groups ranged from 30-34%.
These are the abnormalities that occurred in  1% of in patients indicate a generally similar profile for the active and placebo groups.
Through 48 weeks the profile does not change significantly, and no event appeared dose related.
Based on these safety and efficacy data, the 300 mg dose was evaluated in Study 907.

## Study 907Design

- Randomized, double-blind, placebo-controlled study of TDF added to existing antiretroviral regimens
- Entry criteria:
- Stable ART 8 weeks prior to entry consisting of 4 concomitant antiretroviral agents
- HIV RNA 400 - 10,000 copies/mL
- Primary efficacy endpoint
- Time-weighted average change from baseline in HIV-1 RNA (log10 copies/mL) at week 24 (DAVG24)

**Notes:**
Our Phase III, registrational study.

It was a randomized, double-blind, placebo-controlled study of tenofovir added to an existing regimen.

Similar to Study 902, to enroll patients must have been on a stable regimen for a least 8 weeks of 4 or fewer approved ARTs.

Unlike Study 902, however, we attempted to minimize changes in the background therapy by restricting the upper limit of viral load to 10,000 c/mL, compared to 100,000 in Study 902.

This succeeded in reducing background therapy change to about 10% of patients compared to 30% in Study 902.

Again, the primary efficacy endpoint was DAVG24

## Study 907 Design

**Tenofovir DF 300 mg**

**Placebo**

** ****Tenofovir DF 300 mg**

**Stable ART**
******8 weeks **
**randomized**
**2:1**

**24 wks**

**48 wks**

**48 wks**

**n=550**

**24 wks**

**Double-**
**Blind**

**Open**
**Label**

**Notes:**
Patients were randomized in a 2:1 ratio of active to placebo.

Following 24 weeks of double-blind treatment, all patients received tenofovir 300 mg in an open-label fashion.

550 patients were randomized and received drug.

## Study 907Baseline Characteristics

- 		**Placebo****	****   TDF**
**	****	****(n=182)    ****	****(n=368)**
- Mean age (years)**	**	41		42
- Male**	****	**88%		84%
- Ethnicity
- Caucasian		65%		71%
- African-American                    	 	19%		16%
- Other		16%		13%
- Antiretroviral Regimen
- 	  Protease-containing                 	58%		53%
- 	  NNRTI-containing		36%		43%

**Notes:**
And their baseline characteristics show the two treatment groups were well-matched, with a mean age of about 40, about 15% of the patients were female, and about 30% were non-caucasian.

In addition, the background regimens were similar with respect to the percentage that were receiving a protease inhibitor or non-nucleoside.

## Study 907Baseline HIV Characteristics

- 		**Placebo****	****  TDF**
- Median HIV RNA (copies/mL)	   2340	 2340
- Mean CD4 count (cells/mm3)	     447	   417
- Mean ART use (years)	      5.3	    5.5

**Notes:**
Baseline HIV Characteristics were also well matched, with mean viral loads of about 4,500, and mean CD4 counts, over 400.

These patients were highly treatment-experienced, with an average of about 5 1/2 years of prior antiretroviral use.

## Study 907Virology Substudy

**Primary Resistance Mutations****	****Placebo****	****  ****	****TDF**
- 	NNRTI		52%		46%
- 	PI			62%		57%
- 	NRTI		94%		94%

- Baseline Genotyping (n=253)

**Notes:**
A prospective virology substudy was performed in approximately 1/2 of the patients.

Baseline genotyping identified primary resistance mutations associated with non-nucleosides in about 50% of the patients, protease inhibitors in about 60%, and nucleosides in 94% of patients.

Tenofovir was well tolerated

## 		 Placebo	TDF
Patients who received drug	    182	 368	
Patients discontinued (%)	  11   (6%)	23   (6%)
Adverse event	    5   (3%)	11   (3%)	
Lack of virologic response		 1 (<1%)	  0	
Pregnancy		 1 (<1%)	  1 (<1%)
Lost to follow up		 2   (1%)	  6   (2%)	
Other		 2   (1%)	  5   (1%)	

- Patients who received drug	    182	 368
- Patients discontinued (%)	  11   (6%)	23   (6%)
- Adverse event	    5   (3%)	11   (3%)
- Lack of virologic response		 1 (<1%)	  0
- Pregnancy		 1 (<1%)	  1 (<1%)
- Lost to follow up		 2   (1%)	  6   (2%)
- Other		 2   (1%)	  5   (1%)

- Study 907**Patient Disposition**

- (0-24 weeks)

**Notes:**
as the disposition through 24 weeks shows that 6% of patients in each treatment group discontinued, and 3% in each treatment group discontinued for an adverse event.

and

Tenofovir added to a stable background regimen showed antiviral activity.

## Study 907 Primary Efficacy Endpoint

- 	   **Placebo****	****   TDF**
**	****   ****(n=182)****	****(n=368) ****	****p-value**
- 	    -0.03 		-0.61 	<0.0001

- Mean DAVG24 (log10 copies/mL)

- Intent to Treat

**Notes:**
Analyzing the DAVG24 in the intent-to-treat population, essentially no change was observed in the placebo group compared to a -0.61 reduction in the tenofovir group, which was highly statistically significant.

## Study 907Mean Change from Baseline in HIV-1 RNA

- Intent to Treat

**Notes:**
The addition of tenofovir to, one tablet, once daily, to a background regimen resulted in a rapid decrease in viral load that was maintained through week 24, at which there is approximately 0.6 log decrease.

## Study 907Subgroup Analyses

- 		  	 **Mean DAVG****24**
- 			 **Placebo****	****TDF****	****p-value**
- HIV RNA	<5,000	   0.03	-0.59	<0.0001
-                  5,000	  -0.22	-0.67	<0.0001
- CD4  <200	   0.05	-0.39	<0.0001
- 	      200	  -0.04	-0.64	<0.0001
- Male	  	  -0.02	-0.61	<0.0001
- Female	  	  -0.08	-0.66	<0.0001
- Caucasian	  -0.02	-0.60	<0.0001
- Non-caucasian	  -0.05	-0.65	<0.0001

**Notes:**
Efficacy was also demonstrated in subgroup analyses.

DAVG24 was analyzed by whether patient’s baseline HIV RNA < or > 5,000 copies/mL, CD4 < or > 200 cells/mL, male or female sex, and caucasian or non-caucasian ethnicity.

Tenofovir resulted in decreases in the range of .4 to .7 logs, and in each subgroup the difference was statistically significant.

## Study 907Secondary Efficacy Endpoints

- 	**Placebo ****	****TDF ****	**** p-value**
- HIV RNA  400 copies/mL		13%	45% 	<0.0001
- HIV RNA  50 copies/mL		  1%	22% 	<0.0001
- DAVG24 CD4 (cells/mm3)              -11          +13	  0.0008

- Intent to Treat

**Notes:**
Secondary endpoints further confirmed the activity, with the % < 400 copies/mL 13% in placebo compared to 45% in the tenofovir arm, and the % < 50 is 1% in placebo compared to 22% in the tenofovir arm.

The DAVG24 for CD4 shows a decrease of -11 compared to +13 cells for tenofovir.

Each of these was statistically significant.

The safety profile was similar to placebo.

## Study 907Grade 3/4 Adverse Eventsa

- 		**Placebo****	****  TDF**
**	****	****(n=182)****	****(n=368)**
- Patients (%) with events	24 (13%)	51 (14%)
- 	Diarrhea	  3 (2%)	3 (<1%)
-  	Pain	  2 (1%)	3 (<1%)
- 	Hyperlipidemia	  2 (1%)	2 (<1%)
- 	Nausea	  2 (1%)	2 (<1%)
- 	Depression	  2 (1%)	1 (<1%)
- 	Peripheral neuritis	  2 (1%)	1 (<1%)
- 	Sinusitis	  2 (1%)	1 (<1%)
- 	Gastrointestinal disorder	  2 (1%)	0

*a*  1% in either group

- (0-24 weeks)

**Notes:**
The total percentage of patients with grade 3 or higher clinical adverse events was 13% in the placebo group and 14% in the active.

These events were reported in at least 1% in either group. 

Each of these events occurred at a lower incidence in the tenofovir arm.

## Study 907Grade 3/4 Laboratory Abnormalitiesa

- 		**Placebo****	****   TDF**
**	****	****(n=182)****	****(n=368)**
- Patients (%) with abnormality	68 (37%)	89 (25%)
- 	Triglyceride elevation	24 (13%)	30   (8%)
- 	Creatine kinase elevation	26 (15%)	24   (7%)
- 	Amylase elevation	13   (7%)	21   (6%)
- 	Glucosuria	  6   (3%)	11   (3%)
- 	AST elevation	  5   (3%)	10   (3%)
- 	Hyperglycemia	  8   (4%)	  7   (2%)
- 	ALT elevation	  3   (2%)	  8   (2%)

- (0-24 weeks)

*a*  1% in either group

**Notes:**
Grade 3 or higher laboratory abnormalities were reported in 37% of the placebo group compared to 25% in the tenofovir group.

The abnormalities which occurred in more than 1% of patients have a similar incidence between the groups.

## Renal and Bone Parameters

**Notes:**
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 conducted extensively analyses looking for those toxicities in our clinical studies.

To assess the effects on the kidney, we focused on changes in serum creatinine and phosphorus, 
From an integrated analysis of Studies 902 and 907,  I will present long-term data for those two parameters from the central laboratory database,

and for bone we determined the bone fracture rate.

## Studies 902 and 907Integrated Safety Analysis 

- Includes all patients who received 300 mg (n=687)
- As randomized (n=422)
- Following cross-over from placebo (n=191)
- Following 48 weeks of either 75 or 150 mg (n=74)

**Notes:**
687 patients received the 300 mg dose of tenofovir in Studies 902 and 907.

Of these, 422 patients were randomized to 300 mg.

There were 191 patients following from cross-over placebo, and 74 following 48 weeks of either 75 or 150 mg. 

## Studies 902 and 907Integrated Safety Analysis

- Number of patients			687
- n  48 weeks exposure		480
- n  72 weeks exposure		156
- Mean (weeks)			  58
- Maximum (weeks)			143

**Notes:**
480 patients had at least 48 weeks of tenofovir, and 156 had over 72 weeks exposure.

	Their mean time on tenofovir is 58 weeks and the ranged up to 143 weeks.

## Study 907 Serum Creatinine

**Grade (mg/dL)****	**** Placebo****	****    TDF**
**	****  ****(n=182)****	****  (n=368)**
- 1 ( 0.5 from baseline)	    2 (1%)	   6 (2%)
- 2 (2.1-3.0)	    0	   0
- 3 (3.1-6.0)	    0	   0
- 4 (>6.0)	    0	   0

- Maximum Toxicity Grade(0-24 weeks)

**Notes:**
The maximum toxicity grades for serum creatinine through 24 weeks in Study 907

Shows the incidence of grade 1 was similar, and there were no grade 2 or higher abnormalities

## Studies 902 & 907 Serum Creatinine

**Grade (mg/dL)****	****TDF**
**	****(n=687)**
- 1 ( 0.5 from baseline)	 32 (5%)
- 2 (2.1-3.0)	   0
- 3 (3.1-6.0)	   0
- 4 (>6.0)	   0

- Studies 902 & 907 **Serum Creatinine**

- Maximum Toxicity Grade(0-143 weeks)

**Notes:**
Considering the long-term data 5% had a grade 1 abnormality, but still no patients had grade 2 or higher.

Additional analyses indicate these changes in creatinine are generally transient.

## Studies 902 & 907Consecutive Visits with Grade 1 Creatinine

**32**

**6**

**1**

**1**

- 0

- 5

- 10

- 15

- 20

- 25

- 30

- 35

- Number of patients

****** ****1**

****** ****2**

****** ****3**

**4**

- Visits

**Notes:**
Of the 32 patients with a grade 1 creatinine elevation, 6 had a second consecutive visit with the abnormality.

Of those 6, only 1 patient had 2 additional consecutive visits, and this patient discontinued the study.

At last follow up this patient’s creatinine had returned to the normal range

Similar analysis were performed for serum phosphate.

## Study 907 Serum Phosphorus

**	**** ****Placebo****	****   TDF****	****	**
**Grade (mg/dL)**	 **(n=182)****	**** (n=368)**
- 1 (2.0-2.2)	10   (5%)	  21   (6%)
- 2 (1.5-1.9)	  4   (2%)	  23   (6%)
- 3 (1.0-1.4)	  1 (<1%)	    0
- 4 (<1.0)	  0	  	    1 (<1%)

- Maximum Toxicity Grade(0-24 weeks)

**Notes:**
For hypophosphatemia, 2% of patients in the placebo group compared to 6% in the tenofovir arm had a grade 2 abnormality with only an isolated cases in either arm of grade 3 or 4

## Studies 902 & 907 Serum Phosphorus

**	****    ****TDF**
**Grade (mg/dL)**	** (n=687)**
- 1 (2.0-2.2)	 51   (7%)
- 2 (1.5-1.9)	 58   (8%)
- 3 (1.0-1.4)	   3 (<1%)
- 4 (<1.0)	   1 (<1%)

- Maximum Toxicity Grade(0-143 weeks)

**Notes:**
The longer-term data show the incidence of grade 2 hypophosphatemia has increased slightly, from 6 to 8%, while higher grade abnormalities remained uncommon.

For these 62 patients, additional analyses indicate that the hypophosphatemia is also transient.

## Studies 902 & 907 Consecutive Visits Serum Phosphate <2.0 mg/dL

**62**

**11**

**1**

- 0

- 10

- 20

- 30

- 40

- 50

- 60

- 70

- Number of patients

****** ****1**

****** ****2**

**3**

- Visits

**Notes:**
The bar graphs show the number of patients who had either 1, 2 or 3 consecutive visits with grade 2 or higher hypophosphatemia.

Of those 62 patients 11 had 2 consecutive visits, and only 1 patient had 3, indicating that the hypophosphatemia is transient.

Two patients interrupted dosing, but no patient discontinued tenofovir due to this abnormality.

Overall, there is no indication clinically significant nephrotoxicity associated with tenofovir

	Regarding bone, 

## Studies 902 & 907Bone Fracture Rate

**	****	****	**
**	****	****  ****Total****	****Exposure****	****      No. ****	****	****Fracture**
**	****  ****n ****	****     (patient-yrs)  ****	**** Fractures ****	****	****    Rate*****a*****	****	****	****	**
**Placebo (0-24 wks)****	****210****	****	****  99****	****	****  3****	****  ****	****	****3.0 **
**	**
**TDF (0-143 wks)****	****687****	****	****778****	****	****13****	****  ****	****	****1.7**

***a ***Per 100 patient-years

**Notes:**
Data from studies 902 and 907 indicate tenofovir and placebo have a similar bone fracture rate.

The 210 patients in the placebo group had approximately100 patient-years follow-up and 3 fractures, yielding a fracture rate of 3 per 100 patient-years.

The 687 patients who received tenofovir 300 mg, had more than 7 times the patient years based on a larger patient number and a longer treatment exposure.  13 fractures were reported, and the fracture rate is 1.8.

## Studies 902 and 907Bone Fracture Summary

- External review of radiographs (H. Genant, M.D., UCSF)
- Fractures result of high-impact trauma
- Normal healing observed while TDF continued
- No vertebral compression fractures
- TDF fracture rate is similar to placebo
- Rate has not increased with longer exposure

**Notes:**
Of these 13 fractures, radiographs from 11 have been reviewed by Dr. Harry Genant, Professor of Radiology at UCSF, who has concluded that the fractures are consistent with high impact trauma.

Also, in all 9 cases for which follow-up radiographs, were available, normal healing was observed while patients continued tenofovir dosing.

No vertebral compression fractures, which are typically associated with osteoporosis, have been reported.

As I just showed, the event rate is similar to placebo, and our analyses, with which the agency agrees, indicate the rate has not increased with longer exposure

## Safety Summary

- The safety of TDF 300 mg is similar to placebo through 24 weeks
- The safety profile of TDF shows no significant change with extended dosing

**Notes:**
The safety of tenofovir is similar to placebo through 24 weeks, and shows no significant change with extended dosing

## Efficacy Summary

- TDF 300 mg monotherapy for 28 days resulted in -1.2 log10 copies/mL change from baseline
- Active in highly treatment-experienced patients
- Increases the percentage of patients with HIV RNA  400 and  50 copies/mL
- Consistent across subgroups
- Durable through 48 weeks

**Notes:**
Tenofovir 300 mg is a potent inhibitor of HIV replication, with monotherapy resulting in a 1.2 log decrease from baseline.

Tenofovir added to a background regimen resulted in a significant reduction from baseline of approximately 0.6 logs in highly treatment-experienced patients.

This activity is durable through 48 weeks.

Consistent across subgroups, and increased the percentage of patients with viral loads less than 400 or 50 copies/mL.

As part of our efficacy evaluation we characterized the resistance profile in our clinical virology studies.

## Study 907Virology Substudy

**	****	****     ****Mean DAVG****24 ****(log****10**** c/mL)**
**	****	****	****	****Placebo****	**** TDF**
**Baseline Mutations ****	****	****	****  (n=84)    (n=169)****	****p-value**
**	**
- M184V			 -0.05 	-0.68 		<0.0001
- TAM			+0.03 	-0.47 		<0.0001
- NNRTI - R			+0.02 	-0.49		<0.0001
- PI - R			  0.00	-0.55		<0.0001

- Response by Baseline Resistance MutationsIntent to Treat

**Notes:**
In Study 907 we analyzed DAVG24 according to whether the patient’s HIV expressed  the M184V, any TAM, or any primary resistance mutation to either non-nucleosides or protease inhibitors.  Little change from baseline in the placebo group was observed, compared to reductions in the tenofovir group, ranging from about .5 to .7 logs, which were statistically significant 
Of particular interest is the activity against TAMs

Thymidine analog mutations are now widely recognized to have a crucial role in nucleoside treatment failure.

## VirologyThymidine Analog Mutations (TAMs)

- 6 RT mutations selected in patients receiving ZDV or d4T
- M41L, D67N, K70R, L210W, T215Y/F, K219E/Q/N
- Reduced clinical response to ZDV and d4T
- Also confer cross-resistance to ddI and abacavir (with M184V)

**Notes:**
These mutations are selected in patients receiving zidovudine and d4T, and are associated with a reduced clinical response.

They also confer cross resistance to ddI and, in the presence of M184, abacavir.

## Studies 902 & 907Response by Number of Baseline TAMs

**	****   ****Mean DAVG24**** **
**Baseline Mutations****	****Placebo****	****	****TDF**
**	**** ****(n=110)****	****(n=222)****	****p-value**
- No TAMs	 	-0.11		-0.80	<0.0001
- 1 or 2 TAMs	   -0.04		-0.66	<0.0001
-  3 TAMs	  +0.03		-0.40	<0.0001
-      3 TAMs with M41L or L210W	  +0.01		-0.21	  0.0126
-      3 TAMs / No M41L or L210W	  +0.07		-0.67	<0.0001

- Intent to Treat

**Notes:**
In this exploratory analysis, tenofovir showed a mean DAVG24 reduction for patients whose, of 0.8 for HIV expressed no TAMs, -0.66 for 1 or 2, and -0.4 for 3 or more TAMs.

Upon further analysis, a diminished response was observed when 3 or more TAMs included either M41L or L210W, whereas 3 or more TAMs in the absence of these mutations responded as wild type.

In addition to these genotypic analyses, we also performed phenotypic analyses.

## Studies 902 & 907Response by Baseline Phenotypic Susceptibility

**	****  ****	****Mean DAVG24 **
**Fold change ****	**** n****	****Placebo****	**** TDF**
**from wild-type**
-  1.0 	52	- 0.05	-0.72
- >1.0 and  2.0 	48	+0.03	-0.57
- >2.0 and  3.0 	16	+0.41	-0.51
- >3.0 and  4.0 	  9	    ND***a***	-0.46
- >4.0 	13	-0.22	-0.12

*a*No patients in this group

- Intent to Treat

**Notes:**
In this exploratory analysis, DAVG was also analyzed on the basis of phenotypic susceptibility to tenofovir relative to wild-type virus.

Clinical isolates with up to a 4-fold decreased susceptibility responded to tenofovir with .5 to .7 log reductions, whereas the isolates with > 4-fold change show a diminished response.

## Study 907Virology Substudy

**	****	****Placebo****	****  TDF**
**Mutations ****	**** (n=84)****	****(n=169)**
- PI-related	     8%		 2%
- NNRTI-related	     9%	     5%
- Nucleoside-related	   24%	   16%
- TAMs	   14%	   11%
- K65R	     0	 	 3%

- Development of Resistance Mutations(0-24 weeks)

**Notes:**
We also performed post-baseline genotyping to identify the development of HIV resistance mutations.

Consistent with its antiviral activity Tenofovir suppressed the development of mutations causing resistance to protease inhibitors, non-nucleosides, and nucleosides.

While certain TAM patterns are associated with a reduced response to tenofovir, it did not select for the development of TAMS.

Tenofovir does appear to select for the development of the K65R mutation, as predicted from in vitro studies, but only in 3%.

## Virology Summary

- Active against common HIV resistance mutations, including most TAMs
- Low incidence of TDF resistance mutation development

**Notes:**
Overall, the genotypic analyses demonstrate activity against HIV expressing common resistance mutations, including most TAMs,and there was a low incidence of tenofovir resistance development.

Tenofovir has a very favorable resistance profile, and this enhances its other demonstrated attributes.

## Clinical Conclusions

- Safe and well-tolerated
- Durable antiviral activity

**Notes:**
Tenofovir is safe and well tolerated, provides durable antiviral activity

## Indication

- Tenofovir DF is indicated in combination with other antiretroviral agents for the treatment of HIV infection in adults.
- This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in two controlled trials of 24 and 48 weeks duration in treatment experienced adults with evidence of HIV-1 viral replication despite ongoing antiretroviral therapy.

**Notes:**
Based on these results tenofovir should be indicated in combination with other antiretroviral agents for the treatment of HIV infection in adults.

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

## Tenofovir Disoproxil Fumarate (TDF)

- Overview of Development Program		         Norbert Bischofberger, Ph.D.	**	****	****	****	****	****	**
- Clinical Trial Results                                           Jay Toole, M.D., Ph.D.
**Concluding Remarks                                   ****Norbert Bischofberger, Ph.D.**

## Indication:  Study Design

- Pivotal studies (902 and 907) carried out in treatment-experienced patients
- Unmet medical need
- Resistance profile enables addition of TDF to background therapy
- Intensification design permits clearest assessment of efficacy of TDF

**Notes:**
Dr. Toole has presented safety, efficacy and virology results from our controlled clinical studies 901, 902 and 907 and based on these results we have proposed that TDF should be indicated for the treatment of HIV infection in adults.  In order to further evaluate this indication we need to consider the clinical study design and the population studied.  Both the phase II study 902 and the phase III study 907 were placebo controlled intensification designs carried out in treatment experienced patients.

The reasons why we choose this design is that first this is a patient population with unmet medical need, second this design permits a clear assessment of the efficacy and safety of TDF and third, the resistance profile of TDF allowed for the addition of TD as a single agent to background therapy.

In our studies, we have demonstrated that TDF has antiviral activity in treatment experienced patients which in general is more difficult to achieve than in treatment naïve patients.  However, besides efficacy, TDF fulfills a number of other requirements which support a broader use in treatment naïve patients and our proposed indication.

## Indication:  Supportive Findings

- Use of TDF in treatment-naive patients supported by
- Adherence – once daily dosing
- Low potential for development of resistance mutations
- Safety profile:  No evidence of typical ART dose-limiting toxicities

**Notes:**
One important consideration for naïve patients is adherence - convenience of dosing and pill burden.  TDF meets that requirement since it is dosed as one pill once daily.

Another aspect is development of resistance leading to treatment failure and it can preclude further treatment options.  Our clinical virology data indicate that TDF has a low potential for the development of resistance mutations, particularly TAMs.

Lastly, tolerability and safety are important.  TDF has a safety profile over 24 weeks which is similar to placebo and there is no evidence of typical ART related toxicities.

Given the efficacy of TDF in treatment experienced patients along with meeting these other requirements, TDF should be a treatment choice in naïve patients.

We have three studies currently ongoing or planned which will further provide long term safety and efficacy data for TDF.

## Study 910

- Rollover protocol from studies 901, 902 and 907 (n=575)
- Continuing to evaluate patients through December 2002
- Safety
- Virology
- Bone Mineral Density
- Provides over 4 years of follow up for patients treated with TDF 300 mg

**Notes:**
The first, study 910, is a rollover study for patients who completed studies 901, 902 and 907.  A total of 575 patients enrolled in study 910 and these patients will be evaluated through December 2002 for safety and virology.  This provides over 4 years of follow-up for patients treated with TDF 300 mg.

## Confirmatory Study 903

- EFV + 3TC + d4T  vs.  EFV + 3TC + TDF
- Bone evaluations in all patients
- Bone Mineral Density (DEXA)
- Bone Biomarkers
- Osteocalcin
- Bone-specific alkaline phosphatase
- N and C telopeptides
- Vitamin D
- Parathyroid hormone

**Confirmatory Study 903**

**Notes:**
The second study is study 903, which is also a confirmatory study.  This is a blinded, active controlled study in antiretrovirally naïve patients of 96 weeks duration.  Enrollment in this study is complete with 601 patients.  Patients are randomized in a 1:1 ratio to either EFV + 3TC + D4T or EFC + 3TC + TDF.  The primary endpoints in this study are the proportion of patients with <400 c/mL at week 48 and safety.

In this study extensive bone evaluation will be carried out in all 601 patients, including BMD analysis by Dexa scans and evaluation of biomarkers for both bone formation:  oc, bALP and bone resorption:  urinary N telopeptide and terum C-teleopeptide and VitD and PTH.

Study 903 represents our 1st confirmatory study.  Our 2nd confirmatory study is part of our pediatric development program.

## Pediatric Development

- Pediatric development program initiated following demonstration of safety in adults
- Pediatric formulation in development, available Q1 2002
- Phase I/II studies:
- Study 926:  48 week, PK, safety, efficacy (n=24)
- Study 927:  Single/multiple dose PK (n=30)
- Phase III study:
- 48 week placebo controlled study of TDF added to optimized background regimens
- 2nd confirmatory study

**Notes:**
The evaluation of TDF in pediatric patients has been initiated following demonstration of safety in adults.

A pediatric formulation is in development and will be available in the 1st quarter of next year.

A phase I/II studies have been initiated.  Study 927 in France is evaluating the PK of TDF in 30 pediatric patients and study 926 is a 48 week study at the NCI evaluating PK, safety and efficacy in 24 subjects.

A phase III study is planned.  We propose to the agency a 48 week placebo controlled study where TDF or placebo would be added to OBR.  This would also constitute the 2nd confirmatory study in support of the safety and efficacy of TDF.

These two confirmatory studies and study 910 will further define the long term safety and efficacy of TDF.

Studies presented today have demonstrated that TDF is an effective treatment of HIV infection.

## Conclusions

- Once daily dosing
- No clinically significant drug interactions
- Good tolerability
- Favorable resistance profile
- Durable treatment effect

**Notes:**
In conclusion, we have presented evidence for the safety and efficacy from three placebo controlled studies, study 901, 902 and 907.
There is evidence of longer term safety particularly with regards to renal and bone parameters from the safety update.  Long term safety and efficacy studies study 910 and 903 are ongoing and the pediatric...

With that I would like to close and thank you for your attention.