About Gilead

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About 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

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Worldwide operations
Foster City, CA
San Dimas, CA
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Partners 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)

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Strong infectious disease/antivirals portfolio
Product Indication Status Viread HIV/AIDS Launch
ed in U.S.October 2001 Launch UK 14th February
2002 DaunoXome Kaposis Sarcoma/ AIDS Marketed
Worldwide Vistide CMV Retinitis/
AIDS Marketed U.S. EU Pharmacia AmBisome
Life-threatening Systemic Marketed
Worldwide Fungal Infections Fujisawa
(US) Tamiflu Treatment/ Prevention Marketed
U.S./Japan of Influenza A B EU Approval
Pending (Roche) Adefovir Dipivoxil Chronic HBV
Infection Phase III Complete
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Products in Development
Product Candidate Target Indication Status A
defovir Dipivoxil Hepatitis B Virus Phase
III Cidecin Gram-positive Phase III
(Cubist)(daptomycin for injection) Bacteria
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www.gilead.com
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Gilead in the UK

• HQ in Cambridge
• 43 employees in UK
• Dedicated HIV sales-force of 7

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Community Liaison
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Vancouver 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

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Community Group services

• 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

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Publications
Phoneline
Patients Health Professionals Pharma Industry
Patients Health Professionals


Meetings
Clinical Trial designs


Patients Health Professionals Pharma Industry
Health Professionals Pharma Industry
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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

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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

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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

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Tenofovir DF
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VIREADTM(tenofovir disoproxil fumarate)

• First nucleotide RTI
• One tablet, once daily
• Significant HIV RNA reductions
• Favorable safety profile
• Durable activity against nucleoside-resistant HIV

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Tenofovir 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

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Activation of Competitive RTIs
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Efficiency of Incorporation by Human DNA
Polymerases
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 ? 0.06 0.13 8.00 20.00 25.00
Cihlar, Chen. Antiviral Chem Chemother. 199781.
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Effect of NRTIs on mtDNA Content in Liver and
Muscle Cells
B Skeletal Muscle Cells
A HepG2 Liver Cells
140
140
Abacavir
3TC
Tenofovir
120
120
Tenofovir
3TC
100
Abacavir
100
ZDV
80
80
ZDV
Relative mtDNA content ()
60
60
d4T
d4T
40
40
ddC
ddI
ddI
A
ddC
B
20
20
0
0
0.1
1
10
100
0.1
1
10
100
1000
1000
NRTI concentration (mmol/L)
NRTI concentration (mmol/L)
Birkus G, et al. Antimicrob Agents Chemother.
200246716-723.
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Study 901Median Change from Baseline in HIV
RNA(As-Treated Analysis)
0.25
0
-0.25
placebo
-0.5
75 mg
HIV RNA (log10 c/mL)
-0.75
150 mg
300 mg
-1
600 mg
-1.25
-1.5
0
10
20
30
40
50
60
70
Study Day
Single dose
Once daily dosing
AAC, Oct. 2001 Vol 45, No 10 p2733-2739
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Whats 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

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Study 917 Baseline Characteristics

• Age 34 9 years (range 20 - 48)
• Sex 9 male
• 1 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
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Study 917Mean Change from Baseline in Plasma
HIV-1 RNA (log10 copies/mL)
Mean change from BL at Day 21 -1.5 log10
copies/mL
Louie M , et al. 9th CROI 2002 Seattle, WA.
Presentation 3
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Study 917Relative Efficacy Comparison
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
Louie M , et al. 9th CROI 2002 Seattle, WA.
Presentation 3
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Study 902Mean Change in HIV-1 RNA Week 96
Switch to 300 mg for placebo arm
Switch to 300 mg for all arms
Placebo
Mean Change from Baseline log10 copies/mL
75 mg
150 mg
300 mg
24
48
96
Baseline
n
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
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Study 907 Design
Double- Blind
Open- Label
24 wks
48 wks
Tenofovir DF 300 mg
Stable ART ?8 weeks randomized 21
24 wks
48 wks
Placebo
Tenofovir DF 300 mg
n550
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Study 907 Baseline Characteristics
Tenofovir DF
Placebo
(n368)
(n182)
Mean age (years)
41.3
42.0
male
84
88
Mean HIV-1 RNA (copies/mL)
2340
2340
Mean CD4 count (cells/mm3)
418
447
Mean prior ART use (years)
5.5
5.3
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Study 907Virology Substudy

• n253
• Baseline resistance mutations

NNRTI
48
58
PI
94
NRTI
0
20
40
60
80
100
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Study 907 Patient Disposition
Tenofovir DF at 24 Weeks n368
Placebo at 24 Weeks n182
Tenofovir DF at 48 Weeks n368
11
6
6
Total
3
5
3
Adverse event
0
lt1
Lack of
virologic response
lt1
lt1
lt1
Patient noncompliance
0
2
3
Lost to follow-up
1
lt1
lt1
Pregnancy
lt1
lt1
lt1
Other
1
Squires, CROI
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Mean change from baseline HIV RNA through 48
weeks (ITT) Study 907
9th Conference on Retroviruses and Opportunistic
Infections 2002 Seattle, WA. Abstract 413-W
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Study 907Percentage with HIV-1 RNA lt 400 and lt
50 copies/mLWeek 48 ITT
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Study 907Subgroup Analyses
Mean DAVG24 Placebo TDF p-value HIV
RNA lt5,000 0.03 -0.59 lt0.0001
? 5,000 -0.22 -0.67 lt0.0001 CD4 lt200
0.05 -0.39 lt0.0001 ? 200
-0.04 -0.64 lt0.0001 Male -0.02 -0.61 lt0.0001
Female -0.08 -0.66 lt0.0001 Caucasian
-0.02 -0.60 lt0.0001 Non-caucasian
-0.05 -0.65 lt0.0001
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Study 907DAVG24 in CD4 Cell Count (cells/mm3)48
Week ITT
Tenofovir DF
Placebo
20
13
13
10
DAVG Change in CD4 Cell Count
0
-11
-10
-20
0
4
8
12
16
20
24
28
32
36
40
44
48
Weeks
P0.0008 at week 24.
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Grade 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)
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Studies 902 and 907 Treatment-Related Adverse
Events (Grades 1- 4) Reported in ?3 Patients
(0-24 Weeks)
Tenofovir DF
Placebo Events (n443) (n210) Nausea 1
1 10 Diarrhea 9 8 Asthenia 8 8 Heada
che 6 7 Vomiting 5 2 Flatulence 4 0
Abdominal pain 3 3 Anorexia 3 1
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Incidence of Elevation in Serum Creatinine and
Hypophosphatemia
Tenofovir DF All Placebo 300 mg Tenofovir
DF (0-24 Weeks) (0-24 Weeks) (Mean58 Weeks)
Number of patients 210 443 687 Graded 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 gt6.0 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 lt1 0 lt1 4 lt1.0 0 lt1 lt1
Cheng A, et al. Presented at 9th CROI 2002
Seattle, Wash. Abstract 416-W.
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Studies 902 and 907 Consecutive Visits with
Grade 1 Creatinine
5
4
n687
of patients
3
2
1
0
1
2
3
4
Visits
Patient had pyelonephritis.
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Studies 902 and 907 Consecutive Visits with
Serum Phosphate lt2.0 mg/dL
10
8
n687
6
of patients
4
2
0
1
2
3
Visits
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Studies 902 and 907 Effect of Type and Number of
TAMs on Response (ITT)
n
222
110
42
19
29
57
68
29
55
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0.1
0.0
-0.1
-0.2

Tenofovir DF
-0.3
Placebo
Mean DAVG24 (log10 copies/mL)
-0.4
-0.5
-0.6



-0.7

-0.8
All patients
No TAMs
1 or 2 TAMs
³3 TAMs
³3 TAMs/no
Plt0.0001. P0.013.
with M41L or
M41L or
L210W
L210W
Miller M, et al. Presented at 9th CROI 2002
Seattle, Wash. Abstract 43.
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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 gt1.0 and ? 3.0 49 -0.56 gt3.0 and ?
4.0 7 -0.30 ? 4.0 91 -0.61 gt4.0
9 -0.12
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Two 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

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Chain Terminator Structures
Nucleotide Analog
Nucleoside Analog
O
N
H

2
C
H
3
N
N
N
Phosphonate bond
Phosphate bond
O
N
O
N
O
N
O
P
O
D
N
A
O
O
P
O
D
N
A
Flexibility
C
H

H
O
2
H
O
C

H
3
Bulky N3 radical
Minimal structure (reduced steric bulk)
N
3
Tenofovir
AZT
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TAM 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

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Adjustment by HIV against Competitive RT
Inhibition
NRTIs
NtRTIs
P
P
1 Naeger L.K. et al., Nucleoside RT Inhibitor
removal and nucleoside RT resistance, 41st ICAAC
2001, Pres. 1755
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How do TAMs Mediate Resistance

• 215 base stacking
• Mutation allows close binding of ATP to base
• Proximity catalyses phosphorylysis

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Crystal Structure of Tenofovir DF in HIV RT Shows
Multiple Binding Modes
primer
3
2
3
template
2
1
PMPA-II
tenofovir-I
1
Asp185
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Crystal Structure of Tenofovir DF in HIV RT Shows
Multiple Binding Modes
primer
3
2
3
template
2
1
tenofovir-II
PMPA-I
1
Asp185
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Potential 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

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Study 903 - Design
48 week primary analysis
96 week
d4T, TDF placebo, EFV, 3TC
ART-naïverandomized11
TDF, d4T placebo, EFV, 3TC
n 601
n 601
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Study 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?

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Study 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

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Study 932Design
Randomized 11
TDF 300 mg ddI EC 400 mg (dosed together w/
low fat meal)
TDF 300 mg (fed) ddI EC 400 mg (2 hr prior to
TDF-fasted)
ddI EC washout TDF 300 mg steady-state
ddI EC washout TDF 300 mg steady-state
Single-dose ddI EC 400 mg fasted
Single-dose TDF 300 mg fed
TDF 300 mg ddI EC 400 mg (dosed together w/
low fat meal)
TDF 300 mg (fed) ddI EC 400 mg (2 hr prior to
TDF-fasted)
Day 1 (PK)
Day 8 (PK)
Day 9 (PK)
Days 10-14 (at home)
Day 15 (PK)
Days 2-7 (at home)
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Studies 909 932Tenofovir DF and Didanosine PK
Summary

• ddI EC had no effect on tenofovir PK

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Study 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

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Tenofovir 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