About GileadAbout Gilead

US company with HQ in Foster City, California Founded in 1987

– In-licensed nucleotide technology in ’91– Merged with NeXstar in ’99

Named after the “Balm of Gilead” Focus on life-threatening, hard-to-treat infections Currently employs just over 1000 people globally EU employees have doubled in last year

US company with HQ in Foster City, California Founded in 1987

– In-licensed nucleotide technology in ’91– Merged with NeXstar in ’99

Named after the “Balm of Gilead” Focus on life-threatening, hard-to-treat infections Currently employs just over 1000 people globally EU employees have doubled in last year

Worldwide operations Worldwide operations

PortugalPortugal

ItalyItaly

SpainSpain

GermanyGermany

FranceFrance

Greece Greece

IrelandIreland U.K.U.K.

Foster City, CASan Dimas, CA

Partners and ProductsPartners and Products

Five licensed products– Viread (tenofovir)– AmBisome (liposomal amphotericin B)– DaunoXome (liposomal daunorubicin)– Vistide (cidofovir)– Tamiflu (oseltamivir phosphate)

Licensing partners– AmBisome – Fujisawa (US)– Tamiflu – Roche (US and EU)– Vistide – Pharmacia (EU)– Adefovir – GSK (Asia)

Five licensed products– Viread (tenofovir)– AmBisome (liposomal amphotericin B)– DaunoXome (liposomal daunorubicin)– Vistide (cidofovir)– Tamiflu (oseltamivir phosphate)

Licensing partners– AmBisome – Fujisawa (US)– Tamiflu – Roche (US and EU)– Vistide – Pharmacia (EU)– Adefovir – GSK (Asia)

Strong infectious disease/antivirals portfolio

Product Indication Status

Viread® HIV/AIDS Launched in U.S.October 2001 Launch UK 14th February 2002

DaunoXome® Kaposi’s Sarcoma/ AIDS Marketed Worldwide

Vistide® CMV Retinitis/ AIDS Marketed U.S.EU Pharmacia

AmBisome® Life-threatening Systemic Marketed WorldwideFungal Infections Fujisawa (US)

Tamiflu® Treatment/ Prevention Marketed U.S./Japanof Influenza A & B EU Approval Pending

(Roche)

Adefovir Dipivoxil Chronic HBV Infection Phase III Complete

Products in Development

Product Candidate Target Indication Status

Adefovir Dipivoxil Hepatitis B Virus Phase III

Cidecin™ Gram-positive Phase III (Cubist)(daptomycin for injection) Bacteria

www.gilead.comwww.gilead.com

Gilead in the UKGilead in the UK

HQ in Cambridge

43 employees in UK

Dedicated HIV sales-force of 7

HQ in Cambridge

43 employees in UK

Dedicated HIV sales-force of 7

Community Liaison Community Liaison

Vancouver : Impact of more effective therapyVancouver : Impact of more effective therapy

Increase in number of NGOs involved in treatment education

Increased duplication Risk of assisting those who shout the loudest Risk of pooling funding to one NGO to distribute Less government funding – especially for prevention

Increase in number of NGOs involved in treatment education

Increased duplication Risk of assisting those who shout the loudest Risk of pooling funding to one NGO to distribute Less government funding – especially for prevention

Community Group servicesCommunity Group services

Phoneline Publications

– Conference feedback– Treatment updates– Comments– Education on HIV / adherance / treatments

Meetings Websites Drop ins Support

– Housing– Legal– counselling

Lobbying

Phoneline Publications

– Conference feedback– Treatment updates– Comments– Education on HIV / adherance / treatments

Meetings Websites Drop ins Support

– Housing– Legal– counselling

Lobbying

Beware of duplication• Differentiate• Specialise

Phoneline Publications

Meetings Clinical Trial designs

PatientsHealth Professionals

PatientsHealth Professionals

Pharma Industry

Health ProfessionalsPharma Industry

PatientsHealth Professionals

Pharma Industry

Summary : Role of Community liaison (1)Summary : Role of Community liaison (1)

Advocacy has :– Shaped the regulatory framework in EU and US– Empowered and informed patients– Informed clinicians and improved treatment– Pushed for simpler therapies– Secured NHS funding for treatments– Focused awareness on the developing world

Advocacy has :– Shaped the regulatory framework in EU and US– Empowered and informed patients– Informed clinicians and improved treatment– Pushed for simpler therapies– Secured NHS funding for treatments– Focused awareness on the developing world

Summary : Role of community liaison (2)Summary : Role of community liaison (2)

Advocacy groups are:– Our sternest critics (ethical behaviour)– Our most demanding audience (quality of data)– Our sternest taskmaster (trial needs)– The best conduit of important information to

patients and clinicians The information provided to clinicians is

generally inadequate for the community

Advocacy groups are:– Our sternest critics (ethical behaviour)– Our most demanding audience (quality of data)– Our sternest taskmaster (trial needs)– The best conduit of important information to

patients and clinicians The information provided to clinicians is

generally inadequate for the community

Summary : Role of Community Liaison (3) Summary : Role of Community Liaison (3)

Provide rapid, detailed information on all aspects of a drug

Receive feedback on gaps in clinical development or drug profile

Provide support to the community groups Do all of the above without the promotional

approach of a representative

Provide rapid, detailed information on all aspects of a drug

Receive feedback on gaps in clinical development or drug profile

Provide support to the community groups Do all of the above without the promotional

approach of a representative

Tenofovir DFTenofovir DF

First nucleotide RTI

One tablet, once daily

Significant HIV RNA reductions

Favorable safety profile

Durable activity against nucleoside-resistant HIV

VIREADTM

(tenofovir disoproxil fumarate)VIREADTM

(tenofovir disoproxil fumarate)

Tenofovir DF PharmacologyTenofovir DF Pharmacology

Once-daily dosing– Long intracellular half-life (10-50 hours)

– Terminal serum t½ ~17 hours

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

– No clinically significant drug interactions with EFV, IDV, LPV/r, 3TC; however ddI plasma levels increased ~40% with TDF

Renally cleared– Clearance not affected with co-administration of 3TC or ddI

Oral bioavailability– Fasted state: 25%; fed state: 40%

Once-daily dosing– Long intracellular half-life (10-50 hours)

– Terminal serum t½ ~17 hours

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

– No clinically significant drug interactions with EFV, IDV, LPV/r, 3TC; however ddI plasma levels increased ~40% with TDF

Renally cleared– Clearance not affected with co-administration of 3TC or ddI

Oral bioavailability– Fasted state: 25%; fed state: 40%

Activation of Competitive RTIsActivation of Competitive RTIs

Ph

PP PP PPP

PhP P PhP

NRTIs:

NtRTIs (tenofovir):Cellular enzyme

Cellular enzyme

Cellular enzyme

Cellular enzyme

Cellular enzyme

Cihlar, Chen. Antiviral Chem Chemother. 1997;8:1.

% Incorporation vs Natural Substrate

Substrate

TDFpp

3TC-TP

d4T-TP

ddA-TP

ddC-TP

Pol

1.40

0.05

6.30

0.25

0.10

Pol

1.3

9.0

142.0

80.0

125.0

Pol Pol

0.060.06

0.130.13

8.008.00

20.0020.00

25.0025.00

Efficiency of Incorporation by Human DNA PolymerasesEfficiency of Incorporation by Human DNA Polymerases

A: HepG2 Liver Cells

Birkus G, et al. Antimicrob Agents Chemother. 2002;46:716-723.

1000

NRTI concentration (mol/L)

0.1 1 10 1000

20

40

60

80

100

120

140

Rel

ati

ve

mtD

NA

co

nte

nt

(%)

Tenofovir3TC

Abacavir

ZDV

d4T

ddI ddC

0.1 1 10 100 10000

20

40

60

80

100

120

140

Tenofovir3TC

Abacavir

ZDV

d4T

NRTI concentration (mol/L)

ddI ddC

A B

B: Skeletal Muscle Cells

Effect of NRTIs on mtDNA Content in Liver and Muscle CellsEffect of NRTIs on mtDNA Content in Liver and Muscle Cells

placebo75 mg

150 mg

300 mg

600 mg

Study 901

Median Change from Baseline in HIV RNA(As-Treated Analysis)

-1.5

-1.25

-1

-0.75

-0.5

-0.25

0

0.25

0 10 20 30 40 50 60 70

Study Day

HIV

RN

A (

log

10 c

/mL

)

Single

dose

Once daily dosing

AAC, Oct. 2001: Vol 45, No 10; p2733-2739

What’s the dose?What’s the dose?

The product is made of three elements– Tenofovir – active single phosphonate– Disoproxil – the moiety that shields the

phosphate– Fumarate – the salt used to make the tablet

In each tablet there is– Tenofovir – 136mg– Tenofovir disoproxil – 245mg

• ie 109mg of disoproxil– Tenofovir disoproxil fumarate – 300mg

• ie 55mg of fumarate

The product is made of three elements– Tenofovir – active single phosphonate– Disoproxil – the moiety that shields the

phosphate– Fumarate – the salt used to make the tablet

In each tablet there is– Tenofovir – 136mg– Tenofovir disoproxil – 245mg

• ie 109mg of disoproxil– Tenofovir disoproxil fumarate – 300mg

• ie 55mg of fumarate

Study 917 Baseline CharacteristicsStudy 917 Baseline Characteristics

Age 34 ± 9 years (range 20 - 48)

Sex 9 male1 female

Ethnicity 6 African American 2 Caucasian 1 Asian 1 Hispanic

HIV-1 RNA 4.3 ± 0.5 log10 c/mL (3.7 - 5.0)

CD4 cell count 645 ± 329 cells/mm3 (340 - 1260)

Age 34 ± 9 years (range 20 - 48)

Sex 9 male1 female

Ethnicity 6 African American 2 Caucasian 1 Asian 1 Hispanic

HIV-1 RNA 4.3 ± 0.5 log10 c/mL (3.7 - 5.0)

CD4 cell count 645 ± 329 cells/mm3 (340 - 1260)

Louie M , et al. 9th CROI; 2002; Seattle, WA. Presentation # 3

TDF 300 MG (N=): 10 10 10 10 10 10 10 10 10 10 10 10 10 10

CH

AN

GE

FR

OM

BA

SE

LIN

E H

IV-1

RN

A

-2

-1

0

1

DAYS ON STUDY

BL 1 2 3 4 5 6 7 8 9 10 12 14 21

-2

-1

0

1

Mean change from BL at Day 21 = -1.5 log10 copies/mL

Study 917

Mean Change from Baseline in Plasma HIV-1 RNA (log10 copies/mL)

Study 917

Mean Change from Baseline in Plasma HIV-1 RNA (log10 copies/mL)

Louie M , et al. 9th CROI; 2002; Seattle, WA. Presentation # 3

Regimen Slope RE

LPV/RTV, TDF, EFV, 3TC -0.99/d 1.00

TDF Monotherapy -0.39/d 0.39

RTV Monotherapy -0.34/d 0.34

Study 917

Relative Efficacy ComparisonStudy 917

Relative Efficacy Comparison

Louie M , et al. 9th CROI; 2002; Seattle, WA. Presentation # 3

Study 902

Mean Change in HIV-1 RNA Week 96

Study 902

Mean Change in HIV-1 RNA Week 96

-1

-0.8

-0.6

-0.4

-0.2

0

Baseline 24 48 96

Placebo

75 mg

150 mg

300 mg

Placebo 23 75 mg 48 42 75/300 mg 30 150 mg 45 35 150/300 mg 31300 mg 48 43 300/300 mg 33

n=

Switch to 300 mg for all arms

Switch to 300 mg for placebo arm

Mea

n C

ha

ng

e fr

om

Bas

elin

elo

g1

0 c

op

ies/

mL

Study 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

Open-Label

Tenofovir DF(n=368)

Placebo(n=182)

Mean age (years) 41.3 42.0

Mean HIV-1 RNA (copies/mL) 2340 2340

Mean CD4 count (cells/mm3) 418 447

Mean prior ART use (years) 5.5 5.3

% male 84 88

Study 907 Baseline CharacteristicsStudy 907 Baseline Characteristics

0 20 40 60 80 100

NRTI

PI

NNRTI

58%

48%

94%

Study 907

Virology Substudy Study 907

Virology Substudy

n=253 Baseline resistance mutations

n=253 Baseline resistance mutations

Tenofovir DF at 24 Weeks

n=368

Placeboat 24 Weeks

n=182

Total 6%6%

Adverse event 3%3%

Lack of virologic response 0<1%

Patient noncompliance <1%0

Lost to follow-up 2%1%

Pregnancy <1%<1%

Other <1%1%

Tenofovir DF at 48 Weeks*

n=368

11%

5%

<1%

<1%

3%

<1%

<1%

Study 907 Patient DispositionStudy 907 Patient Disposition

* Squires, CROI

Mean change from baseline HIV RNA through 48 weeks (ITT) Study 907Mean change from baseline HIV RNA through 48 weeks (ITT) Study 907

9th Conference on Retroviruses and Opportunistic Infections; 2002; Seattle, WA. Abstract 413-W

Study 907Percentage with HIV-1 RNA < 400 and < 50 copies/mLWeek 48: ITT

Study 907Percentage with HIV-1 RNA < 400 and < 50 copies/mLWeek 48: ITT

Study 907

Subgroup AnalysesStudy 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

-20

-10

0

10

20

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

Weeks

DA

VG

Ch

ang

e in

CD

4 C

ell C

ou

nt

Tenofovir DFPlacebo

+13

-11

P=0.0008 at week 24.

+13

Study 907DAVG24 in CD4 Cell Count (cells/mm3)48 Week: ITT

Study 907DAVG24 in CD4 Cell Count (cells/mm3)48 Week: ITT

Grade 3 and 4 Adverse Events and Laboratory AbnormalitiesGrade 3 and 4 Adverse Events and Laboratory Abnormalities

Table 2 — Grade 3 or 4 adverse events and laboratory abnormalities (occurring in 2% of patients in any group)

Studies 902 and 907

Treatment-Related Adverse Events (Grades 1- 4) Reported in 3% Patients

Studies 902 and 907

Treatment-Related Adverse Events (Grades 1- 4) Reported in 3% Patients

Tenofovir DF PlaceboEvents (n=443) (n=210)

Nausea 11% 10%

Diarrhea 9% 8%

Asthenia 8% 8%

Headache 6% 7%

Vomiting 5% 2%

Flatulence 4% 0%

Abdominal pain 3% 3%

Anorexia 3% 1%

(0-24 Weeks)

Incidence of Elevation in Serum Creatinine and Hypophosphatemia Incidence of Elevation in Serum Creatinine and Hypophosphatemia

Tenofovir DF All Placebo 300 mg Tenofovir DF

(0-24 Weeks) (0-24 Weeks) (Mean=58 Weeks)

Number of patients 210 443 687Graded serum creatinine (mg/dL)

1 0.5 over baseline 1% 1% 5%2 2.1-3.0 0% 0% 0%3 3.1-6.0 0% 0% 0%4 >6.0 0% 0% 0%

Graded hypophosphatemia (mg/dL)1 2.0-2.2 5% 6% 7%2 1.5-1.9 2% 6% 8%3 1.0-1.4 <1% 0% <1%4 <1.0 0% <1% <1%

Cheng A, et al. Presented at: 9th CROI; 2002; Seattle, Wash. Abstract 416-W.

0

1

2

3

4

5

% o

f p

atie

nts

1 2 3* 4*Visits

*Patient had pyelonephritis.

Studies 902 and 907: Consecutive Visits with Grade 1 CreatinineStudies 902 and 907: Consecutive Visits with Grade 1 Creatinine

n=687

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

0.1

All patients No TAMs 1 or 2 TAMs 3 TAMswith M41L or

L210W

3 TAMs/noM41L orL210W

Tenofovir DF

Placebo

Studies 902 and 907: Effect of Type and Number of TAMs on Response (ITT)

Mea

n D

AV

G24

(lo

g10

co

pie

s/m

L)

222 110 42 19295768 29 55 33n =

*

** *

**

*P0.0001.**P=0.013.Miller M, et al. Presented at: 9th CROI; 2002; Seattle, Wash. Abstract 43.

HIV RNA Response at Week 24 by Baseline VIREAD Susceptibility in Studies 902 and 907 (Intent to Treat)

HIV RNA Response at Week 24 by Baseline VIREAD Susceptibility in Studies 902 and 907 (Intent to Treat)

Change in HIV RNA

Baseline Susceptibility n TDF 1.0 35 -0.74

>1.0 and 3.0 49 -0.56

>3.0 and 4.0 7 -0.30

4.0 91 -0.61

>4.0 9 -0.12

Two Major Mechanisms for NRTI Drug ResistanceTwo Major Mechanisms for NRTI Drug Resistance

Removal of chain terminator by phosphorolysis– TAMs– 69 insertions– Mechanism most involved in cross-resistance

Reduced binding of chain terminator– M184V– Q151M– L74V– K65R

Removal of chain terminator by phosphorolysis– TAMs– 69 insertions– Mechanism most involved in cross-resistance

Reduced binding of chain terminator– M184V– Q151M– L74V– K65R

N

N

O

CH3

O

OO

N3

P

O

HO

ODNAN

NN

N

NH 2

O

C H 3

CH 2

PO

HO

O

DNA

TenofovirTenofovir AZTAZT

Nucleotide Analog Nucleoside Analog

Chain Terminator StructuresChain Terminator Structures

Phosphonate bond Phosphate bond

Flexibility

Bulky N3 radical

Minimal structure(reduced steric bulk)

TAM Mediated ResistanceTAM Mediated Resistance

Problem:– In the presence of multiple TAMs (41,67, 70,

210, 215, 219) ZDV sensitivity 100-fold– Incorporation of ZDV into DNA only 2-fold

Solution:– Enzyme catalysed base pairing is running in

reverse - Phosphorylysis

Problem:– In the presence of multiple TAMs (41,67, 70,

210, 215, 219) ZDV sensitivity 100-fold– Incorporation of ZDV into DNA only 2-fold

Solution:– Enzyme catalysed base pairing is running in

reverse - Phosphorylysis

Adjustment by HIV against Competitive RT InhibitionAdjustment by HIV against Competitive RT Inhibition

PP

PPP

Pyrophosphorylyse(meist ATP-abhängiger Ausbau falscher DNA-Bausteine)

+

DNA synthesis continues

Ph

Pyrophosphorylyse aufgrund des Phosphonatrests und des azyklischen „Linkers“ deutlich erschwert1.

DNA synthesis remains blocked

NRTIs NtRTIs

P P

1: Naeger L.K. et al., Nucleoside RT Inhibitor removal and nucleoside RT resistance, 41st ICAAC 2001, Pres. 1755

How do TAMs Mediate ResistanceHow do TAMs Mediate Resistance

215 base stacking

– Mutation allows close binding of ATP to base

– Proximity catalyses phosphorylysis

215 base stacking

– Mutation allows close binding of ATP to base

– Proximity catalyses phosphorylysis

tenofovir-I

template

PMPA-II

Asp185

primer

1

2

3

3’

2’

1’

Crystal Structure of Tenofovir DF in HIV RT Shows Multiple Binding ModesCrystal Structure of Tenofovir DF in HIV RT Shows Multiple Binding Modes

PMPA-I

template

tenofovir-II

Asp185

primer

1

2

3

3’

2’

1’

Crystal Structure of Tenofovir DF in HIV RT Shows Multiple Binding ModesCrystal Structure of Tenofovir DF in HIV RT Shows Multiple Binding Modes

Potential Basis for Lower Cross-resistance to Tenofovir DFPotential Basis for Lower Cross-resistance to Tenofovir DF

Unique phosphonate bond is less susceptible to ATP-mediated phosphorolysis– Tenofovir is 20- to 35-fold less efficiently

removed than d4T and AZT by the mutant RT containing multiple TAMs

Tenofovir lacks the steric bulk that could favor excision or reduce incorporation into viral DNA

Multiple RT binding modes may provide an unfavorable environment for excision of tenofovir or for resistance due to steric hindrance

Unique phosphonate bond is less susceptible to ATP-mediated phosphorolysis– Tenofovir is 20- to 35-fold less efficiently

removed than d4T and AZT by the mutant RT containing multiple TAMs

Tenofovir lacks the steric bulk that could favor excision or reduce incorporation into viral DNA

Multiple RT binding modes may provide an unfavorable environment for excision of tenofovir or for resistance due to steric hindrance

Study 903 - DesignStudy 903 - Design

96 week48 weekprimary analysis

n = 601n = 601

d4T, TDF placebo, EFV, 3TC

ART-naïverandomized

1:1

TDF, d4T placebo, EFV, 3TC

Study 932: TDF-ddI BackgroundStudy 932: TDF-ddI Background

Study 909: Videx buffered tablets– Increased ddI exposure (Cmax 28%, AUC 44%)

Study 932: Assess interaction w/Videx EC

Administration ddI EC w/food reduces ddI exposures– What is effect of simultaneous administration ddI EC

and Viread and a meal?

Study 909: Videx buffered tablets– Increased ddI exposure (Cmax 28%, AUC 44%)

Study 932: Assess interaction w/Videx EC

Administration ddI EC w/food reduces ddI exposures– What is effect of simultaneous administration ddI EC

and Viread and a meal?

Study 932 ObjectivesStudy 932 Objectives

Determine PK of tenofovir and ddI following administration of ddI EC and TDF alone and in pairs in healthy subjects

– Staggered co-administration of ddI EC + TDF, with ddI EC administered in the fasted state and TDF taken w/ a meal

– Simultaneous administration ddI EC and Viread and a meal

Determine PK of tenofovir and ddI following administration of ddI EC and TDF alone and in pairs in healthy subjects

– Staggered co-administration of ddI EC + TDF, with ddI EC administered in the fasted state and TDF taken w/ a meal

– Simultaneous administration ddI EC and Viread and a meal

Study 932Design

Day 1

(PK)

Day 8

(PK)

Day 9

(PK)

Randomized 1:1

TDF 300 mg+

ddI EC 400 mg(dosed together w/

low fat meal)ddI EC washout

TDF 300 mg

steady-state

Single-dose

ddI EC 400 mgfasted

TDF 300 mg (fed)+

ddI EC 400 mg(2 hr prior to TDF-

fasted)

TDF 300 mg+

ddI EC 400 mg(dosed together w/

low fat meal)

ddI EC washout

TDF 300 mg

steady-state

Single-dose

TDF 300 mg fed

Days 10-14

(at home)

Day 15

(PK)

TDF 300 mg (fed) +

ddI EC 400 mg(2 hr prior to TDF-

fasted)

Days 2-7

(at home)

Studies 909 & 932

Tenofovir DF and Didanosine PK Summary

Studies 909 & 932

Tenofovir DF and Didanosine PK Summary

TDF + Difference in ddI Cmax Difference in ddI AUC

ddI (buffered tablets)Study 909 +28 +44

ddI EC separated by 2 hrs +48 +48

ddI EC simultaneously w/food +64 + 60

• ddI EC had no effect on tenofovir PK

Study 932 ConclusionsStudy 932 Conclusions

Co-administration of ddI EC w/ TDF resulted in 48% higher didanosine levels– Similar to results observed with Videx– Likely due to increased oral bioavailability of

ddI

Co-administration of ddI EC w/ TDF resulted in 48% higher didanosine levels– Similar to results observed with Videx– Likely due to increased oral bioavailability of

ddI

Tenofovir Indication in US and EUTenofovir Indication in US and EU

US

“Viread is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection”

EU

“Viread is indicated in combination with other antiretroviral agents in HIV infected patients over 18 years of age experiencing virological failure”

US

“Viread is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection”

EU

“Viread is indicated in combination with other antiretroviral agents in HIV infected patients over 18 years of age experiencing virological failure”