Transcript No Slide Title

About Gilead
 US company with HQ in Foster City, California
 Founded in 1987
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

– 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
Ireland
U.K.
Germany
Foster City, CA
San Dimas, CA
France
Portugal
Italy
Spain
Greece
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)
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
Fungal Infections
Marketed Worldwide
Fujisawa (US)
Tamiflu®
Treatment/ Prevention
of Influenza A & B
Marketed U.S./Japan
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
(daptomycin for injection) Bacteria
Phase III (Cubist)
www.gilead.com
Gilead in the UK
 HQ in Cambridge
 43 employees in UK
 Dedicated HIV sales-force of 7
Community Liaison
Vancouver :
Impact of more effective therapy
 Increase in number of NGOs involved in treatment
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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 services
 Phoneline
 Publications
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
Beware of duplication
• Differentiate
• Specialise
– Conference feedback
– Treatment updates
– Comments
– Education on HIV / adherance / treatments
Meetings
Websites
Drop ins
Support
– Housing
– Legal
– counselling
Lobbying
Phoneline
Patients
Health Professionals
Meetings
Patients
Health Professionals
Pharma Industry
Publications
Patients
Health Professionals
Pharma Industry
Clinical Trial
designs
Health Professionals
Pharma Industry
Summary : Role of Community liaison (1)
 Advocacy has :
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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)
 Advocacy groups are:
–
–
–
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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)
 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 DF
VIREADTM
(tenofovir disoproxil fumarate)
 First nucleotide RTI
 One tablet, once daily
 Significant HIV RNA
reductions
 Favorable safety profile
 Durable activity against
nucleoside-resistant HIV
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%
Activation of Competitive RTIs
NRTIs:
Cellular
enzyme
Cellular
enzyme
P P
P
NtRTIs (tenofovir):
Cellular
enzyme
Cellular
enzyme
Ph
P P P
Cellular
enzyme
P Ph
P P Ph
Efficiency of Incorporation by Human
DNA Polymerases
% Incorporation vs Natural Substrate
Pol 
Pol 
Pol 
TDFpp
1.40
1.3
0.06
3TC-TP
0.05
9.0
0.13
d4T-TP
6.30
142.0
8.00
ddA-TP
0.25
80.0
20.00
ddC-TP
0.10
125.0
25.00
Substrate
Cihlar, Chen. Antiviral Chem Chemother. 1997;8:1.
Effect of NRTIs on mtDNA Content in
Liver and Muscle Cells
B: Skeletal Muscle Cells
Relative mtDNA content (%)
A: HepG2 Liver Cells
140
120
3TC
Tenofovir
100
Abacavir
80
ZDV
60
d4T
40
20
A
ddC
ddI
0
140
Abacavir
120
Tenofovir
3TC
ZDV
100
80
60
d4T
40
20
ddC
ddI
B
0
0.1
1
10
100 1000
NRTI concentration (mmol/L)
Birkus G, et al. Antimicrob Agents Chemother. 2002;46:716-723.
0.1
1
10
100
1000
NRTI concentration (mmol/L)
Study 901
Median Change from Baseline in HIV RNA
As-Treated Analysis)
0.25
HIV RNA (log10 c/mL)
0
-0.25
placebo
75 mg
150 mg
300 mg
600 mg
-0.5
-0.75
-1
-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
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
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
Study 917
Mean Change from Baseline in
Plasma HIV-1 RNA (log10 copies/mL)
CHANGE FROM BASELINE HIV-1 RNA
1
1
Mean change from BL at Day
21 = -1.5 log10 copies/mL
0
0
-1
-1
-2
-2
BL
1
2
3
4
5
6
7
8
9
10
12
14
21
10
10
DAYS ON STUDY
TDF 300 MG (N=):
10 10 10 10 10 10 10 10 10 10 10
Louie M , et al. 9th CROI; 2002; Seattle, WA. Presentation # 3
10
Study 917
Relative 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
Study 902
Mean Change in HIV-1 RNA
Week 96
Switch to 300 mg
for placebo arm
Switch to 300 mg
for all arms
Mean Change from Baseline
log10 copies/mL
0
n=
Placebo
75 mg
150 mg
300 mg
-0.2
Placebo
75 mg
150 mg
300 mg
-0.4
-0.6
-0.8
-1
Baseline
24
23
48
45
48
48
96
42
35
43
75/300 mg 30
150/300 mg 31
300/300 mg 33
Study 907
Design
DoubleBlind
OpenLabel
24 wks
48 wks
Tenofovir DF 300 mg
Stable ART
8 weeks
randomized
2:1
24 wks
Placebo
n=550
48 wks
Tenofovir DF 300 mg
Study 907
Baseline Characteristics
Mean age (years)
Tenofovir DF
Placebo
(n=368)
(n=182)
41.3
42.0
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
% male
Study 907
Virology Substudy
 n=253
 Baseline resistance mutations
NNRTI
48%
58%
PI
94%
NRTI
0
20
40
60
80
100
Study 907
Patient Disposition
Placebo
at 24 Weeks
n=182
Tenofovir DF
at 24 Weeks
n=368
Tenofovir DF
at 48 Weeks*
n=368
Total
6%
6%
11%
Adverse event
3%
3%
5%
Lack of virologic response <1%
0
<1%
<1%
<1%
Patient noncompliance
0
Lost to follow-up
1%
2%
3%
<1%
<1%
<1%
1%
<1%
<1%
Pregnancy
Other
* Squires, CROI
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
Study 907
Percentage with HIV-1 RNA
< 400 and < 50 copies/mL
Week 48: ITT
Study 907
Subgroup Analyses
Mean DAVG24
Placebo TDF
p-value
HIV RNA <5,000
 5,000
0.03
-0.22
-0.59
-0.67
<0.0001
<0.0001
CD4 <200
 200
0.05
-0.04
-0.39
-0.64
<0.0001
<0.0001
Male
Female
-0.02
-0.08
-0.61
-0.66
<0.0001
<0.0001
Caucasian
Non-caucasian
-0.02
-0.05
-0.60
-0.65
<0.0001
<0.0001
Study 907
DAVG24 in CD4 Cell Count (cells/mm3)
DAVG Change in CD4 Cell Count
48 Week: ITT
Tenofovir DF
Placebo
20
+13
+13
10
0
-11
-10
-20
0
4
8 12 16 20 24 28 32 36 40 44 48
P=0.0008 at week 24.
Weeks
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)
Studies 902 and 907
Treatment-Related Adverse Events (Grades 1- 4)
Reported in 3% Patients
(0-24 Weeks)
Tenofovir DF
Events
Nausea
Diarrhea
Asthenia
Headache
Vomiting
Flatulence
Abdominal pain
Anorexia
(n=443)
11%
9%
8%
6%
5%
4%
3%
3%
Placebo
(n=210)
10%
8%
8%
7%
2%
0%
3%
1%
Incidence of Elevation in Serum
Creatinine and Hypophosphatemia
Placebo
(0-24 Weeks)
Number of patients
Graded serum creatinine (mg/dL)
1 0.5 over baseline
2 2.1-3.0
3 3.1-6.0
4 >6.0
Graded hypophosphatemia (mg/dL)
1 2.0-2.2
2 1.5-1.9
3 1.0-1.4
4 <1.0
Tenofovir DF
300 mg
All
Tenofovir DF
(0-24 Weeks)
(Mean=58 Weeks)
210
443
687
1%
0%
0%
0%
1%
0%
0%
0%
5%
0%
0%
0%
5%
2%
<1%
0%
6%
6%
0%
<1%
7%
8%
<1%
<1%
Cheng A, et al. Presented at: 9th CROI; 2002; Seattle, Wash. Abstract 416-W.
Studies 902 and 907: Consecutive Visits
with Grade 1 Creatinine
% of patients
5
4
n=687
3
2
1
0
1
*Patient had pyelonephritis.
2
3*
Visits
4*
Studies 902 and 907: Effect of Type and Number of
TAMs on Response (ITT)
n=
222
110
68
29
55
33
57
29
42
19
0.1
Mean DAVG24 (log10 copies/mL)
0.0
-0.1
-0.2
**
Tenofovir DF
Placebo
-0.3
-0.4
-0.5
-0.6
*
*
-0.7
*
*
-0.8
All patients
No TAMs
1 or 2 TAMs
3 TAMs
*P<0.0001.
with M41L or
L210W
**P=0.013.
Miller M, et al. Presented at: 9th CROI; 2002; Seattle, Wash. Abstract 43.
3 TAMs/no
M41L or
L210W
HIV RNA Response at Week 24 by Baseline VIREAD
Susceptibility in Studies 902 and 907
(Intent to Treat)
Change in HIV RNA
Baseline Susceptibility
 1.0
>1.0 and  3.0
n
35
49
TDF
-0.74
-0.56
7
-0.30
 4.0
91
-0.61
>4.0
9
-0.12
>3.0 and  4.0
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
Chain Terminator Structures
Nucleotide Analog
Nucleoside Analog
NH 2
O
CH 3
N
N
N
Phosphonate bond
Phosphate bond
O
O
N
DNA
DNA
O
P
N
O
N
O
P
O
O
O
CH2
Flexibility
HO
HO
CH
3
Bulky N3 radical
Minimal structure
(reduced steric bulk)
Tenofovir
N3
AZT
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
Adjustment by HIV against Competitive
RT Inhibition
NRTIs
NtRTIs
P
Ph
Pyrophosphorylyse
(meist ATP-abhängiger
Ausbau falscher DNABausteine)
P P
+
Pyrophosphorylyse
aufgrund des
Phosphonatrests und
des azyklischen
„Linkers“ deutlich
erschwert1.
P P P
DNA synthesis continues
DNA synthesis remains blocked
1: Naeger L.K. et al., Nucleoside RT Inhibitor removal and nucleoside RT resistance, 41st ICAAC 2001, Pres. 1755
How do TAMs Mediate Resistance
 215 base stacking
– Mutation allows close binding of ATP to base
– Proximity catalyses phosphorylysis
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
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
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
Study 903 - Design
48 week
primary analysis
d4T, TDF placebo, EFV, 3TC
ART-naïve
randomized
1:1
TDF, d4T placebo, EFV, 3TC
n = 601
96 week
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?
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
Study 932
Design
Randomized 1:1
TDF 300 mg
+
ddI EC 400 mg
(dosed together w/
low fat meal)
Singledose
ddI EC
400 mg
fasted
TDF 300 mg (fed)
+
ddI EC 400 mg
(2 hr prior to TDFfasted)
ddI EC
washout
ddI EC
washout
TDF 300 mg
steady-state
TDF 300
mg
steadystate
TDF 300 mg (fed)
+
ddI EC 400 mg
(2 hr prior to TDFfasted)
TDF 300 mg
+
ddI EC 400 mg
(dosed together w/
low fat meal)
Singledose
TDF 300
mg fed
Day 1
Days 2-7
Day 8
Day 9
Days 10-14
Day 15
(PK)
(at home)
(PK)
(PK)
(at home)
(PK)
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 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
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”