1 tenofovir disoproxil fumarate nda 21-356 october 3, 2001 gilead sciences, inc. foster city, ca

1

Tenofovir Disoproxil Fumarate

NDA 21-356

October 3, 2001

Gilead Sciences, Inc.

Foster City, CA

2

Gilead Consultants

Harry K. Genant, M.D.Professor of Radiology, Orthopedic Surgery and MedicineUniversity 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 MedicineUniversity of Colorado Health Sciences Center

Steven L. Teitelbaum, M.D.Wilma and Roswell Messing Professor of Pathology and ImmunologyWashington University, St. Louis

3

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.

4


• Orally bioavailable prodrug of tenofovir (PMPA)

• Nucleotide RTI

• One tablet, once daily

• Durable activity against nucleoside resistant HIV

N

NN

N

NH2

OP

OO

O

O

O

O

O

O

O

5

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

6Susceptibility of Nucleoside-Resistant

HIV-1 Clinical Isolates (Virco)

0.7 0.60.7

1.7

0.1

1.0

10.0

100

3.0 2.5

M184V(n=10)

L74V(n=5)

L74V + Y115F + M184V(n=5)

Q151MComplex

(n=10)

K65R(n=8)

T69 Insertions

(n=15)

Fo

ld C

han

ge

fro

m W

ild

-Typ

e

11.7

Normal Range (< 3-fold)

Resistant (> 10-fold)Intermediate Susceptibility (3-10-fold)

T215Y +other TAMs(n=20)

3.1

7

Pharmacology

• Once-daily dosing

– Long intracellular half-life (10-50 hours)

– Terminal serum t½ ~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)

8

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

9

NDA Safety Database

Patients receiving 300 mga

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)

10





11

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

12Study 901Design

• 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

13Study 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%

14Study 901HIV 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

15Study 901

Mean Change from Baseline in HIV-1 RNAIntent to Treat

Placebo 11TDF 75 mg 12TDF 150 mg 8TDF 300 mg 8TDF 600 mg 10

9 12 7 8 9

8 12 8 8 8

9 12 8 8 9

8 11 8 7 8

9 10 8 8 8

9 10 8 7 7

8 11 8 7 4

SingleDose

Daily Dosing

OffTreatment

BL 4 8 14 21 28 35 42 63

-1.5

-1.0

-0.5

0.0

0.5

Days

Me

an

lo

g10

co

pie

s/m

L

PlaceboTDF 75 mgTDF 150 mgTDF 300 mgTDF 600 mg

16Study 902Design

• 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)

17Study 902Design

Stable ART 8 weeks

randomized2:2:2:1

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

18Study 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)

19Study 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)

20Study 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)

21Study 902

Primary Efficacy Endpoint

TDFPlacebo 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)

22Study 902


28Placebo 27 27 26 26 22 23 0 0 05375 mg 49 53 49 48 49 48 49 46 4251150 mg 48 49 49 46 44 45 42 39 3554300 mg 51 52 52 50 49 48 49 43 43

Me

an

lo

g10

co

pie

s/m

L

Weeks

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

BL1 2 4 8 12 16 20 24 32 40 481 2 4 8 12 16 20 24 32 40 481 2 4 8 12 16 20 24 32 40 481 2 4 8 12 16 20 24 32 40 48

Placebo75 mg

150 mg300 mg

23Study 902

CD4 Count

TDFPlacebo 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

24Study 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)

25

TDF 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 902Grade 3/4 Laboratory Abnormalitiesa

a 1% in any group

(0 - 24 weeks)

26Study 907Design

• 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)

27Study 907 Design

Tenofovir DF 300 mg

Placebo Tenofovir DF 300 mg

Stable ART8 weeks

randomized2:1

24 wks

48 wks

48 wks

n=550

24 wks

Double-Blind

OpenLabel

28Study 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%

29Study 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

30Study 907

Virology Substudy

Primary Resistance Mutations Placebo TDF

NNRTI 52% 46%

PI 62% 57%

NRTI 94% 94%

Baseline Genotyping (n=253)

31

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%)

Study 907Patient Disposition

(0-24 weeks)

32Study 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

33Study 907


TDF 300 mg 368Placebo 182

335170

358179

353175

354175

353173

346173

346172

HIV-1 RNAlog10 c/mL(95% CI)

Weeks 0 2 4 8 12 16 20 24

-0.8

-0.6

-0.4

-0.2

0.0

0.2

TDF 300 mg

Placebo

34Study 907

Subgroup Analyses

Mean DAVG24

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 <0.0001Female -0.08 -0.66 <0.0001

Caucasian -0.02 -0.60 <0.0001Non-caucasian -0.05 -0.65 <0.0001

35Study 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

36Study 907

Grade 3/4 Adverse Eventsa


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


(0-24 weeks)

37Study 907

Grade 3/4 Laboratory Abnormalitiesa


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)


Renal and Bone Parameters

39Studies 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)


Integrated Safety Analysis

Number of patients 687

n 48 weeks exposure 480

n 72 weeks exposure 156

Mean (weeks) 58

Maximum (weeks) 143

41Study 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)

42

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 CreatinineMaximum Toxicity Grade

(0-143 weeks)

43Studies 902 & 907

Consecutive Visits with Grade 1 Creatinine

32

6

1 10

5

10

15

20

25

30

35

Num

ber

of p

atie

nts

1

2 3 4Visits

44Study 907

Serum Phosphorus

Placebo TDFGrade (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%)


45Studies 902 & 907

Serum Phosphorus

TDFGrade (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%)


46Studies 902 & 907 Consecutive Visits Serum

Phosphate <2.0 mg/dL

62

11

10

10

20

30

40

50

60

70

Num

ber

of p

atie

nts

1 2 3Visits

47Studies 902 & 907

Bone Fracture Rate

Total Exposure No. Fracture n (patient-yrs) Fractures Ratea

Placebo (0-24 wks) 210 99 3 3.0

TDF (0-143 wks) 687 778 13 1.7

a Per 100 patient-years


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

49

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

50

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

51Study 907Virology Substudy

Mean DAVG24 (log10 c/mL)

Placebo TDFBaseline 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

52Virology

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)

53Studies 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

54Studies 902 & 907

Response by Baseline Phenotypic Susceptibility

Mean DAVG24

Fold change n Placebo TDFfrom 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 NDa -0.46

>4.0 13 -0.22 -0.12

aNo patients in this group

Intent to Treat

55Study 907Virology Substudy

Placebo TDFMutations (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)

56

Virology Summary

• Active against common HIV resistance mutations, including most TAMs

• Low incidence of TDF resistance mutation development

57

Clinical Conclusions

• Safe and well-tolerated

• Durable antiviral activity

58

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.

59





60

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

61

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

62

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

63

• Blinded, active-controlled, ART-naïve patients, 96 weeks, n=601

• 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

64

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

65

Conclusions

• Once daily dosing

• No clinically significant drug interactions

• Good tolerability

• Favorable resistance profile

• Durable treatment effect

1 tenofovir disoproxil fumarate nda 21-356 october 3, 2001 gilead sciences, inc. foster city, ca

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