Introduction

Geraldine Reilly

Gilead Science

Objectives

To review TDF interaction data

To review triple nucleoside data

To discuss the relevance of these data to clinical practice

To present the EMTRIVA dataset

To discuss questions regarding Emtriva and requirements for additional data or information

To review TDF safety data

Nucleoside (cytosine) analogue

One capsule, once daily, without food restrictions

Long intracellular half-life

Significant HIV RNA reductions

Favorable safety profile

Durable efficacy and safety in treatment-naïve and treatment-experienced patients

EMTRIVA™

(emtricitabine)

Mean Steady-State Plasma Emtricitabine Concentration Following 200 mg QD Dose

0.001

0.01

0.1

1

10

0 24 48 72 96 120

Time (hrs post dose)

Pla

sma

Em

tric

itab

ine

Co

nc

(µg

/mL

)

Mean In Vitro IC90

Mean In Vitro IC50

Plasma half-life ~ 10 hours

Wang L, et al. XIV International AIDS Conference, Barcelona 2002, Poster #4546

Intracellular FTC-TP Concentration Following 200 mg QD Dose¹

0.01

0.1

1

10

0 24 48 72 96 120

Time (hrs post dose)

FTC-TP mean half-life ~ 39 hours

1Wang L, et al. XIV International AIDS Conference, Barcelona 2002, Poster #45462Moore K., et al, AIDS 1999;13:2239-50

3TC-TP mean half-life ~ 16 hours²

FT

C-5

'-T

P C

on

c in

PB

MC

(p

mo

le/1

06 cel

ls

Pharmacokinetic Considerations for Approved and Investigational Once-daily NRTIs

0

5

10

15

20

25

30

35

40

45

50

ZDV d4T ABC 3TC FTC

Serum half-life Intracellular half-life

Hou

rs

Investigational Approved Approved Approved ApprovedQD as QD or BID as QD or BID as QD as QD

24 hours

12 hours

Centers for Disease Control and Prevention. MMWR Recomm Rep. 2002;51(RR-7):1-64

TDFddI

* Piliero, et al. 43rd ICAAC, Chicago, 2003. ** Anderson, et al. AIDS 2003; 17(15):2159-2168.

Indicates range where available

* **

**

Forgiveness and Once-dailyAntiretroviral Therapy (ART)

0 24 483612

Time (hours)

QD long half-life

BID

Dru

g c

on

cen

trat

ion

Zone of potential replication

IC90

IC50

Missed Dose

Day 1 Day 2Hypothetical and not

representative of specificARV agents

QD short half-life

Emtricitabine Pharmacology

Once-daily dosing– Serum t1/2 10 hours

– Long intracellular half-life (FTC-TP); t1/2 39 hours

Can be taken without regard to food– 93% in fed or fasted state

Renally cleared– 83% cleared through the kidneys

• Dosage reduction required in renally impaired patients

Few drug interactions– Not a substrate or inhibitor of human CYP450 enzymes

– No known clinically significant drug interactions

Pregnancy Category B

3TC and ABC naiveMonotherapy 10-day dosing vs 3TC (n=81)

Study 102

3TC and ABC naiveMonotherapy 14-day dosing (n=41)

Study 101

Patient PopulationDesign

EmtricitabineMonotherapy Studies

Study 101Emtricitabine Antiviral Activity During Short Term (14 days) Monotherapy

Mea

n C

han

ge

in H

IV-1

RN

A (

log

10)

25 mg bid (n = 9)

100 mg qd (n = 8)

100 mg bid (n = 8)

0.5

0.0

–0.5

–1.0

–1.5

–2.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Study Day

200 mg qd (n = 8)

200 mg bid (n = 8)

-1.92 log

F. Rousseau, et al. JAC(2001) 48, 507-513

Study 102Emtricitabine Antiviral Activity Compared to Lamivudine150 mg BID in Short Term (10 Days) Monotherapy

0

–0.5

–1.0

–1.5

–2.0

1 2 3 4 5 6 7 8 9 10 11 12

3TC 150 mg bid (n=20)FTC 25 mg qd (n=21)FTC 100 mg qd (n=19)FTC 200 mg qd (n=21)

Study Day

Mea

n C

han

ge

i n

HI V

- 1 R

NA

(L

og

1 0)

Delehanty J. et al, 6th CROI. Chicago 1999. Abstract #16

*p<0.05 for FTC 200 mg QD compared to each of the other treatment arms

-1.7 log

-1.5 logp<0.05*

Study 102Emtricitabine Antiviral Activity Compared to Lamivudine150 mg BID in Short Term (10 Days) Monotherapy

0

–0.5

–1.0

–1.5

–2.0

1 2 3 4 5 6 7 8 9 10 11 12

3TC 150 mg bid (n=20)

FTC 200 mg qd (n=21)

Study Day

Mea

n C

han

ge

i n

HI V

- 1 R

NA

(L

og

1 0)

Delehanty J. et al, 6th CROI. Chicago 1999. Abstract #16

*p<0.05 for FTC 200 mg QD compared to each of the other treatment arms

-1.7 log

-1.5 logp<0.05*

Summary: Preclinical and PK

In vitro preclinical findings

– 10-fold greater relative substrate specificity for HIV-1 RT than 3TC

– 24-fold less relative substrate specificity for mtDNA gamma polymerase

Pharmacokinetics clearly support QD dosing

– Plasma half life of 10 hours with linear kinetics and plasma values > IC90 ~ 84 hrs

– Triphosphate intra-cellular half life ~ 39 hrs Potent antiviral activity

– 1.92 log10 reduction in plasma HIV-1 RNA after 14 days of monotherapy (FTC-101)

– Statistically greater reduction in plasma HIV-1 RNA after 10 days of monotherapy compared to 3TC (FTC-102)

HIV RNA <400 copies/ml

CD4: no restriction

3TC switch to FTC in 3TC-stable patients(n=440)

Study 303

Patient PopulationDesign

Clinical Program Overview:Efficacy and Safety Studies

HIV RNA <400 copies/ml

CD4: no restriction

PI switch to FTC/ddI/EFV (n=355)

ANRS 099(Alize)

Treatment-Naïve Studies

Switch Studies

HIV RNA >5000 copies/ml

CD4: no restriction

FTC vs d4T [+ddI/EFV] (n=571)

Study 301

HIV RNA >5000 copies/ml

CD4 >100 cells/mm³

FTC/ddI/EFV - Open Label (n=40)

ANRS 091(MONTANA)

Study 301

Study 301 Study Design

ART-naive patients

(N = 571)

randomized 1:1,

double-blind

FTC 200 mg QDddI QDEFV QDd4T placebo BID

d4T BIDddI QDEFV QDFTC placebo QD

Week 48

Week 48

Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.

Study 301 Baseline Characteristics

4041HIV-1 RNA >100,000 (%)

324312Mean CD4 count (cells/mm3)

4.84.8Mean HIV-1 RNA (log10)

56%48%Caucasian

86%84%Male

3636Mean age (y)

d4T+ddI+EFV (n=285)

FTC+ddI+EFV (n=286)

Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.

Study 301

Patient Disposition at Week 48

*p<0.05

FTC+ddI+EFV (n=286)

d4T+ddI+EFV (n=285)

Patients Discontinued from Study * 49 (17%) 78 (27%)

D/C due to Adverse Event* 16 (6%) 33 (12%)

Treatment Failure* 8 (3%) 22 (8%)

Other 25 (9%) 23 (8%)

LTFU 9 (3%) 12 (4%)

Request for withdrawal 5 (2%) 4 (1%)

Protocol Violation 7 (2%) 2 (<1%)

Noncompliance 2 (<1%) 3 (1%)

Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48

Weeks

% P

atie

nts

wit

h H

IV-1

RN

A <

50

cop

ies/

mL

d4T+ddI+EFVFTC+ddI+EFV

BL

74%

58%

p = 0.0001

Intent to Treat (Missing = Failure)

Study 301 % Patients < 50 copies/mL

Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48

Weeks

% P

atie

nts

wit

h H

IV-1

RN

A <

50

cop

ies/

mL

BL

91%

84%

d4T+ddI+EFVFTC+ddI+EFV

As Treated (Missing = Excluded)

p<0.05

Data on file. Gilead Sciences, Inc. June 2003.

Study 301 % Patients < 50 copies/mL

Study 301 Mean Change From Baseline in Absolute CD4+

0

40

80

120

160

200

BL 4 8 12 16 20 24 28 32 36 40 44 48

Weeks

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

- A

bs

olu

te C

D4

+ C

ell

Co

un

t

d4T+ddI+EFVFTC+ddI+EFV

168

134

p = <0.05

Intent to Treat (Missing = Failure)

Data on file. Gilead Sciences, Inc. June 2003.

* Reported in > 3% of FTC-treated patients in Study 301 or 303 Only events that occurred in > 10% in either arm were analyzed for statistical significance.

p<0.05* *

26%21%19%13%12%13%

25%16%11%4%6%9%

DizzinessInsomniaAbnormal dreams**Neuropathy/Peripheral neuritis**Paresthesia**Depressive disorders

32%23%12%12%

23%13%8%9%

Diarrhea**Nausea**DyspepsiaVomiting

17%25%17%

14%22%12%

Abdominal PainHeadacheAsthenia

D4T+ddI+EFV(n=285)

FTC + ddI + EFV (n=286)Adverse Events

Study 301Selected* Treatment-Emergent Adverse EventsThrough 48 Weeks (All Grades, Regardless of Causality)

p<0.05* *

3%6%

6%5%

MyalgiaArthralgia

10%8%

12%14%

RhinitisIncreased cough**

33%30%Rash event

D4T+ddI+EFV(n=285)

FTC + ddI + EFV (n=286)Adverse Events

Study 301Selected* Treatment-Emergent Adverse EventsThrough 48 Weeks (All Grades, Regardless of Causality)

* Reported in > 3% of FTC-treated patients in Study 301 or 303 Only events that occurred in > 10% in either arm were analyzed for statistical significance.

<1%<1%Bilirubin (>2.5 x ULN)

6%5%ALT (>5.0 x ULN)

9%6%AST (>5.0 x ULN)

11%12%Creatinine Kinase (>4.0 x ULN)

38%34%Percentage with Grade 3 or Grade 4 laboratory abnormality

D4T+ddI+EFV(n=285)

FTC + ddI + EFV (n=286)Number of Patients Treated

* Reported in > 1% of FTC-treated patients in Study 301 or 303** Only events that occurred in > 10% in either arm were analyzed for statistical significance.

Study 301 Treatment-Emergent Grade 3/4 Laboratory Abnormalities* Through 48 Weeks

7%5%Neutrophils (<750 mm3)

6%9%Triglycerides (>750 mg/dL)

3%2%Serum Glucose (<40 or >250 mg/dL)

1%<1%Pancreatic amylase (>2.0 x ULN)

10%5%Serum amylase (>2.0 x ULN)**

2%1%Serum lipase (>2.0 x ULN)

D4T+ddI+EFV(n=285)

FTC + ddI + EFV (n=286)Number of Patients Treated

p<0.05* *

* Reported in > 1% of FTC-treated patients in Study 301 or 303 Only events that occurred in > 10% in either arm were analyzed for statistical significance.

Study 301 Treatment-Emergent Grade 3/4 Laboratory Abnormalities* Through 48 Weeks, Cont

Study 301Virology

FTC-resistant isolates have been selected in vitro – Genotypic analyses demonstrated M184V or M184I mutation

37.5 % (6/16) of isolates from FTC-treated patients with virologic failure in study 301 showed reduced susceptibility to FTC associated with the development of the M184V/I mutation

Interim Analysis: – After last enrolled patient completed 24-weeks of treatment– Median duration of follow-up was 42-weeks– Efficacy and safety data– Results presented at the 42nd ICAAC, September 2002

DSMB Recommendation:– Termination of the double-blind comparative phase of study– d4T-treatment group discontinued and all patients offered open-label

access to the FTC-treatment group

Study Completion: – After last enrolled patient completed 48-weeks of treatment – Median duration of follow-up was 60-weeks– Update of efficacy and results

Study 301DSMB Interim Analysis Review

FTC in Treatment-naïve Patients: Conclusions

FTC+ddI+EFV is a convenient, potent and well- tolerated once-daily regimen in ARV-naïve patients

– Durable efficacy reported to 3 years (MONTANA)

Once-daily FTC demonstrated superior efficacy and safety as compared to twice-daily d4T (FTC 301)

Dose and Dose Interval Adjustments of NRTIs for Patients with Renal Impairment

Drug Renal Impairment

CBV Not recommended

TZV Not recommended

AZT Dose adjust per guidelines

3TC Dose adjust per guidelines

FTC Dose interval adjust per guidelines

TDF Dose interval adjust per guidelines

d4T Dose adjust per guidelines

ddI EC Dose adjust per guidelines

ABC Unknown

Emtricitabine: Dose Interval Adjustment in Renal Impairment

ARV Pregnancy Categorization

Category B: TDF, FTC, ddI

- NFV, RTV, SQV, T-20

Category C: CBV, TRZ, 3TC, AZT, d4T, ABC, ddC

- DLV, NVP, EFV, APV, IDV, IDV/r, fos-APV/r

Category D: Hydroxyurea

FDA Pregnancy Categories – Definitions*

A: Controlled studies in women in first trimester show no risk

B: Animal studies do not indicate risk OR human studies show no risk to fetus (although animal studies may show adverse effect)

C: Animal studies show adverse effects (teratogenic or embryocidal); no controlled studies in pregnant women; weigh benefits versus risks

D: Positive evidence of human risk; benefits may outweigh risks for serious diseases where alternatives not available

X: Risk shown; risk outweighs benefit

*FDA Federal Register

Hyperpigmentation

Hyperpigmentation was rare and generally mild and non-progressive– 3% (29/814) of patients in studies 301,302,303– 28/29 Grade 1; 1/29 Grade 2– Only 2 progressed from Grade 1 to 2

Observed primarily on the palms/soles after 3 months– Median time to onset 88 days– Occurred at a higher rate in black patients (8%)

Never required FTC discontinuation

Resolved in some patients (5/29) while on treatment

Emtricitabine NDA filing June 2003

Hyperpigmentation of the Palms

Nail Discoloration Observed with AZT

Observed primarily on fingernails and toenails1-3

– Color ranges from dark brown to purple1-3

Onset: 4 months to 1 year after starting AZT1-4

Incidence:– In a study of Combivir (AZT/3TC) + ABC, the

incidence of nail discoloration was 5.7%4

– In two retrospective studies, the incidence was 42% and 39%, respectively2,3

• Of those who developed it, 67-82% were African American2,3

1 Rahav et l. Scan J Infect Dis 1992; 24:557-612 Groark et al. J Am Acad Dermatol 1989; 21:1032-3

3 Don et al. Ann Intern Med 1990; 112-145-64 GlaxoWellcome Medical Information

Emtricitabine Virology

Triple NRTI ComparisonsIncidence of the M184V/I Mutation in Patients who Experienced Virological Failure

52%

74%78%

73%

67% 67%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

FTC +d4T+ABC

All 3TC +AZT+ABC

CNAAB3005 CNAA3003 EPV40001 QD EPV40001 BID

p < 0 .02

• Incidence of M184V/I mutation was significantly lower for FTC regimen compared to 3TC+ AZT+ ABC regimens (-21% treatment difference with a 95% CI [-37%, -5%]; p 0.02)

Sanne I, et al. 43rd ICAAC, Chicago, 2003, #H-868.

Historical Studies of ABC/3TC/ZDV

Future StudiesDiscussion

The Future: TDF/FTC Fixed Dose Combination Tablet

Tenofovir and Emtricitabine fixed dose combination

Study 934 in progressTDF/FTC/EFV vs COM/EFV

Bioequivalence and stability studies in progress

Other Studies

TDF + FTC backbone --– What other studies should be performed to better

characterize the clinical role of this NRTI backbone?

– Specific regimens or third agents?– Different patient populations?– Other?

Other Studies

EMTRIVA --– What other studies should be performed to better

characterize Emtriva and its place in clinical care?

– Comparative trials?– Different patient populations?– Other?

Emtriva & VireadSummary of Similar Characteristics

Durable efficacy in clinical trials– Both Emtriva and Viread have shown efficacy in both treatment-naïve

and treatment-experienced patients

Tolerability and safety

Convenience– Both one tablet dosed once-daily

Pharmacokinetics– Both have long intracellular half-lives, true once-daily dosing– Both can be taken without regard to food

Co-infection– Though not indicated for hepatitis B, both have demonstrated potency

against hepatitis B in co-infected patients

Thank you!