Gilead Sciences
About Gilead
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Worldwide operations
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
Partners and Products
!
Ireland
Ireland
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)
U.K.
U.K.
Germany
Germany
Foster City, CA
San Dimas, CA
France
France
Portugal
Portugal
Italy
Italy
Spain
Spain
Greece
Greece
Strong infectious disease/antivirals portfolio
Products in Development
Product
Indication
Status
Viread ®
HIV/AIDS
Launched in U.S.October 2001
Launch UK 14 th February 2002
DaunoXome ®
Kaposi’s Sarcoma/ AIDS
Marketed Worldwide
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
Vistide
®
Product Candidate
Target Indication
Adefovir Dipivoxil
Hepatitis B Virus
Gram-positive
Cidecin ™
(daptomycin for injection) Bacteria
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Status
Phase III
Phase III (Cubist)
Gilead Sciences
www.gilead.com
Gilead in the UK
!
HQ in Cambridge
!
43 employees in UK
!
Dedicated HIV sales-force of 7
Vancouver :
Impact of more effective therapy
!
Community Liaison
Liaison
!
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!
!
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 services
!
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!
!
Phoneline
Beware of duplication
Publications
• Differentiate
– Conference feedback
• Specialise
– 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
Page ‹#›
Publications
Patients
Health Professionals
Pharma Industry
Clinical Trial
designs
Health Professionals
Pharma Industry
Gilead Sciences
Summary : Role of Community liaison (1)
Summary : Role of community liaison (2)
(2)
!
!
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 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)
!
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 t__ ~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
!
Oral bioavailability
– Clearance not affected with co-administration of 3TC or ddI
– Fasted state: 25%; fed state: 40%
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Gilead Sciences
Efficiency of Incorporation by Human
DNA Polymerases
Activation of Competitive RTIs
NRTIs:
% Incorporation vs Natural Substrate
Cellular
enzyme
Cellular
enzyme
Cellular
enzyme
P P
P
NtRTIs (tenofovir):
Cellular
enzyme
Ph
Pol α
Pol β
Pol γ
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
P P P
Cellular
enzyme
P Ph
P P Ph
Cihlar, Chen. Antiviral Chem Chemother. 1997;8:1.
Study 901
Effect of NRTIs on mtDNA Content in
Liver and Muscle Cells
Abacavir
100
80
ZDV
60
d4T
40
20
A
ddC
ddI
0
0.25
0
140
HIV RNA (log 10 c/mL)
Relative mtDNA content (%)
3TC
Tenofovir
120
As-Treated Analysis)
B: Skeletal Muscle Cells
A: HepG2 Liver Cells
140
Median Change from Baseline in HIV RNA
Abacavir
120
Tenofovir
3TC
ZDV
100
80
60
20
ddC
-1
ddI
-1.5
B
0
0
0.1
1
10
100 1000
NRTI concentration (µmol/L)
placebo
75 mg
150 mg
300 mg
600 mg
-0.5
-0.75
-1.25
d4T
40
-0.25
0.1
1
10
100
10
20
30
40
50
60
70
1000
NRTI concentration (µmol/L)
Study Day
Single
dose
Once daily
dosing
Birkus G, et al. Antimicrob Agents Chemother. 2002;46:716-723.
AAC, Oct. 2001: Vol 45, No 10; p2733-2739
Study 917
What’s the dose?
Baseline Characteristics
!
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
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
c/mL (3.7 - 5.0)
4.3 ± 0.5 log 10
10
CD4 cell count
645 ± 329 cells/mm 33 (340 - 1260)
Louie M , et al. 9th CROI; 2002; Seattle, WA. Presentation # 3
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Gilead Sciences
Study 917
Mean Change from Baseline in
Plasma HIV-1 RNA (log10 copies/mL)
Study 917
Relative Efficacy Comparison
CHANGE FROM BASELINE HIV-1 RNA
1
1
Mean change from BL at Day
21 = -1.5 log 10 copies/mL
0
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
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
10
Louie M , et al. 9th CROI; 2002; Seattle, WA. Presentation # 3
Louie M , et al. 9th CROI; 2002; Seattle, WA. Presentation # 3
Study 902
Study 907
Mean Change in HIV-1 RNA
Design
Week 96
Switch to 300 mg
for placebo arm
Switch to 300 mg
for all arms
DoubleBlind
Mean Change from Baseline
log10 copies/mL
0
n=
Placebo
75 mg
150 mg
300 mg
24 wks
-0.2
-0.4
Placebo
75 mg
-0.6
150 mg
300 mg
48 wks
Tenofovir DF 300 mg
Stable ART
≥8 weeks
randomized
2:1
24 wks
Placebo
-0.8
-1
Baseline
OpenLabel
48 wks
Tenofovir DF 300 mg
n=550
24
23
48
45
48
48
96
42
35
43
75/300 mg 30
150/300 mg 31
300/300 mg 33
Study 907
Study 907
Baseline Characteristics
Virology Substudy
!
Tenofovir DF Placebo
(n=368)
Mean age (years)
% male
41.3
!
n=253
Baseline resistance mutations
(n=182)
42.0
84
88
Mean HIV-1 RNA (copies/mL)
2340
2340
Mean CD4 count (cells/mm 3)
418
447
Mean prior ART use (years)
5.5
5.3
NNRTI
48%
58%
PI
94%
NRTI
0
Page ‹#›
20
40
60
80
100
Gilead Sciences
Mean change from baseline HIV RNA
through 48 weeks (ITT) Study 907
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%
Lack of virologic response <1%
5%
0
<1%
<1%
<1%
Patient noncompliance
0
Lost to follow-up
1%
2%
3%
<1%
<1%
<1%
1%
<1%
<1%
Pregnancy
Other
* Squires, CROI
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
Study 907
Subgroup Analyses
Week 48: ITT
Mean DAVG24
Study 907
DAVG Change in CD4 Cell Count
48 Week: ITT
20
+13
10
0
-11
-20
0
4
8 12 16 20 24 28 32 36 40 44 48
P=0.0008 at week 24.
-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
Table 2 — Grade 3 or 4 adverse events and laboratory abnormalities
(occurring in ≥ 2% of patients in any group)
Tenofovir DF
Placebo
-10
p-value
0.03
-0.22
Grade 3 and 4 Adverse Events and
Laboratory Abnormalities
DAVG24 in CD4 Cell Count (cells/mm3)
+13
Placebo TDF
HIV RNA <5,000
≥ 5,000
Weeks
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Gilead Sciences
Studies 902 and 907
Incidence of Elevation in Serum
Creatinine and Hypophosphatemia
Treatment-Related Adverse Events (Grades 1- 4)
Reported in ≥3% Patients
(0-24 Weeks)
Tenofovir DF
Events
Placebo
(n=443)
(n=210)
11%
9%
8%
6%
5%
4%
3%
3%
10%
8%
8%
7%
2%
0%
3%
1%
Nausea
Diarrhea
Asthenia
Headache
Vomiting
Flatulence
Abdominal pain
Anorexia
Tenofovir DF
300 mg
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
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
Studies 902 and 907: Consecutive Visits
with Serum Phosphate <2.0 mg/dL
10
% of patients
% of patients
5
4
n=687
3
2
8
n=687
6
4
2
1
0
1
2
3*
0
4*
1
Visits
*Patient had pyelonephritis.
2
3
Visits
Studies 902 and 907: Effect of Type and Number of
TAMs on Response (ITT)
HIV RNA Response at Week 24 by Baseline VIREAD
Susceptibility in Studies 902 and 907
(Intent to Treat)
n=
222
110
68
29
55
33
57
29
42
19
Mean DAVG 24 (log 10 copies/mL)
0.1
Change in HIV RNA
0.0
Baseline Susceptibility
≤ 1.0
>1.0 and ≤ 3.0
-0.1
-0.2
**
Tenofovir DF
Placebo
-0.3
>3.0 and ≤ 4.0
-0.4
-0.5
-0.6
*
*
-0.7
*
*
-0.8
All patients
No TAMs
1 or 2 TAMs
≥3 TAMs
with M41L or
L210W
*P<0.0001.
**P=0.013.
Miller M, et al. Presented at: 9th CROI; 2002; Seattle, Wash. Abstract 43.
≥3 TAMs/no
M41L or
L210W
Page ‹#›
n
35
49
TDF
-0.74
-0.56
7
-0.30
≤ 4.0
91
-0.61
>4.0
9
-0.12
Gilead Sciences
Two Major Mechanisms for NRTI
Drug Resistance
Chain Terminator Structures
Nucleotide Analog
!
Removal of chain terminator by phosphorolysis
– TAMs
– 69 insertions
– Mechanism most involved in cross-resistance
! Reduced binding of chain terminator
– M184V
– Q151M
– L74V
– K65R
Nucleoside Analog
NH 2
CH 3
N
N
N
Phosphonate bond
Phosphate bond
O
N
O
DNA
DNA
O
P
P
O
O
O
O
CH 2
Flexibility
HO
HO
CH 3
Bulky N 3 radical
Minimal structure
(reduced steric bulk)
N3
AZT
Adjustment by HIV against Competitive
RT Inhibition
TAM Mediated Resistance
NRTIs
!
N
O
N
Tenofovir
!
O
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
NtRTIs
P
Ph
Pyrophosphorylyse
(meist ATP-abhängiger
Ausbau falscher DNABausteine)
Solution:
– Enzyme catalysed base pairing is running in
reverse - Phosphorylysis
Pyrophosphorylyse
aufgrund des
Phosphonatrests und
des azyklischen
„Linkers“ deutlich
erschwert 1.
P P
+
P PP
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
Crystal Structure of Tenofovir DF in HIV RT
Shows Multiple Binding Modes
How do TAMs Mediate Resistance
primer
!
215 base stacking
3’
– Mutation allows close binding of ATP to base
– Proximity catalyses phosphorylysis
2’
3
template
2
1’
PMPA-II
tenofovir-I
1
Asp185
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Gilead Sciences
Potential Basis for Lower
Cross-resistance to Tenofovir DF
Crystal Structure of Tenofovir DF in HIV RT
Shows Multiple Binding Modes
primer
!
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
3’
2’
3
template
2
1’
tenofovir-II
PMPA-I
1
Asp185
Study 932: TDF-ddI Background
Study 903 - Design
48 week
primary analysis
96 week
! Study 909: Videx buffered tablets
28%, AUC 44%)
– Increased ddI exposure (C max
max
d4T, TDF placebo, EFV, 3TC
! Study 932: Assess interaction w/Videx EC
ART-naïve
randomized
1:1
! Administration ddI EC w/food reduces ddI exposures
– What is effect of simultaneous administration ddI EC
and Viread and a meal?
TDF, d4T placebo, EFV, 3TC
n = 601
Study 932
Design
Study 932 Objectives
Randomized 1:1
! Determine PK of tenofovir and ddI following administration
TDF 300 mg
+
ddI EC 400 mg
(dosed together w/
low fat meal)
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
Singledose
ddI EC
400 mg
fasted
– Simultaneous administration ddI EC and Viread and a
meal
Page ‹#›
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)
Gilead Sciences
Studies 909 & 932
Study 932 Conclusions
Tenofovir DF and Didanosine PK Summary
TDF +
ddI (buffered tablets)
Study 909
Difference in ddI Cmax
Difference in ddI AUC
+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
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”
Page ‹#›
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