Geraldine Reilly

1
Introduction

• Geraldine Reilly
• Gilead Science

2
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

3
EMTRIVA(emtricitabine)

• 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

4
Mean Steady-State Plasma Emtricitabine
Concentration Following 200 mg QD Dose
10
1
Plasma half-life 10 hours
Plasma Emtricitabine Conc (µg/mL)
0.1
Mean In Vitro IC90
0.01
Mean In Vitro IC50
0.001
0
24
48
72
96
120
Time (hrs post dose)
Wang L, et al. XIV International AIDS Conference,
Barcelona 2002, Poster 4546
5
Intracellular FTC-TP Concentration Following 200
mg QD Dose¹
10
FTC-TP mean half-life 39 hours
1
FTC-5'-TP Conc in PBMC (pmole/106cells
0.1
3TC-TP mean half-life 16 hours²
0.01
0
24
48
72
96
120
Time (hrs post dose)
1Wang L, et al. XIV International AIDS
Conference, Barcelona 2002, Poster 4546
2Moore K., et al, AIDS 1999132239-50
6
Pharmacokinetic Considerations for Approved and
Investigational Once-daily NRTIs
Investigational Approved Approved Approved App
roved QD as QD or BID as QD or BID as QD as QD
50
45
40
35
30
Hours
25
24 hours
20
15
12 hours
10
5
0
ZDV
d4T
ABC
3TC
FTC
TDF
ddI
Indicates range where available
Serum half-life
Intracellular half-life
Piliero, et al. 43rd ICAAC, Chicago, 2003.
Anderson, et al. AIDS 2003 17(15)2159-2168.
Centers for Disease Control and Prevention. MMWR
Recomm Rep. 200251(RR-7)1-64
7
Forgiveness and Once-dailyAntiretroviral Therapy
(ART)
Missed Dose
Day 1
Day 2
Hypothetical and notrepresentative of
specificARV agents
Drug concentration
IC90
Zone of potential replication
IC50
12
0
24
48
36
Time (hours)
8
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

9
EmtricitabineMonotherapy Studies
Patient Population
Design
3TC and ABC naive
Monotherapy 14-day dosing (n41)
Study 101
3TC and ABC naive
Monotherapy 10-day dosing vs 3TC (n81)
Study 102
10
Study 101Emtricitabine Antiviral Activity During
Short Term (14 days) Monotherapy
0.5
25 mg bid (n 9)
100 mg qd (n 8)
0.0
100 mg bid (n 8)
200 mg qd (n 8)
Mean Changein HIV-1 RNA (log10)
0.5
200 mg bid (n 8)
1.0
1.5
-1.92 log
2.0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Study Day
F. Rousseau, et al. JAC(2001) 48, 507-513
11
Study 102Emtricitabine Antiviral Activity
Compared to Lamivudine150 mg BID in Short Term
(10 Days) Monotherapy
0
3TC 150 mg bid (n20)
FTC 25 mg qd (n21)
0.5
FTC 100 mg qd (n19)
FTC 200 mg qd (n21)
Mean Change in HIV-1 RNA (Log10)
1.0
plt0.05
-1.5 log
1.5
-1.7 log
2.0
1
2
3
4
5
6
7
8
9
10
11
12
Study Day
plt0.05 for FTC 200 mg QD compared to each of the
other treatment arms
Delehanty J. et al, 6th CROI. Chicago 1999.
Abstract 16
12
Study 102Emtricitabine Antiviral Activity
Compared to Lamivudine150 mg BID in Short Term
(10 Days) Monotherapy
0
3TC 150 mg bid (n20)
0.5
FTC 200 mg qd (n21)
Mean Change in HIV-1 RNA (Log10)
1.0
plt0.05
-1.5 log
1.5
-1.7 log
2.0
1
2
3
4
5
6
7
8
9
10
11
12
Study Day
plt0.05 for FTC 200 mg QD compared to each of the
other treatment arms
Delehanty J. et al, 6th CROI. Chicago 1999.
Abstract 16
13
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 gt 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)

14
Clinical Program OverviewEfficacy and Safety
Studies
Patient Population
Design
Treatment-Naïve Studies
Switch Studies
HIV RNA lt400 copies/ml CD4 no restriction
PI switch to FTC/ddI/EFV (n355)
ANRS 099(Alize)
HIV RNA lt400 copies/ml CD4 no restriction
3TC switch to FTC in 3TC-stable patients(n440)
Study 303
15
Study 301
16
Study 301 Study Design
Week 48
ART-naive patients (N 571) randomized 11,
double-blind
Week 48
Cahn P, et al. 10th CROI, Boston, 2003, Poster
606.
17
Study 301 Baseline Characteristics
d4TddIEFV (n285)
FTCddIEFV (n286)
36
36
Mean age (y)
86
84
Male
56
48
Caucasian
4.8
4.8
Mean HIV-1 RNA (log10)
324
312
Mean CD4 count (cells/mm3)
40
41
HIV-1 RNA gt100,000 ()
Cahn P, et al. 10th CROI, Boston, 2003, Poster
606.
18
Study 301Patient Disposition at Week 48
plt0.05
Cahn P, et al. 10th CROI, Boston, 2003, Poster
606.
19
Study 301 Patients lt 50 copies/mL
Cahn P, et al. 10th CROI, Boston, 2003, Poster
606.
20
Study 301 Patients lt 50 copies/mL
plt0.05
Data on file. Gilead Sciences, Inc. June 2003.
21
Study 301 Mean Change From Baseline in Absolute
CD4
Data on file. Gilead Sciences, Inc. June 2003.
22
Study 301Selected Treatment-Emergent Adverse
EventsThrough 48 Weeks (All Grades, Regardless
of Causality)
plt0.05
Reported in gt 3 of FTC-treated patients in
Study 301 or 303 Only events that occurred in
gt 10 in either arm were analyzed for statistical
significance.
23
Study 301Selected Treatment-Emergent Adverse
EventsThrough 48 Weeks (All Grades, Regardless
of Causality)
plt0.05
Reported in gt 3 of FTC-treated patients in
Study 301 or 303 Only events that occurred in
gt 10 in either arm were analyzed for statistical
significance.
24
Study 301 Treatment-Emergent Grade 3/4
Laboratory Abnormalities Through 48 Weeks
Reported in gt 1 of FTC-treated patients in
Study 301 or 303 Only events that occurred in
gt 10 in either arm were analyzed for statistical
significance.
25
Study 301 Treatment-Emergent Grade 3/4
Laboratory Abnormalities Through 48 Weeks, Cont
plt0.05
Reported in gt 1 of FTC-treated patients in
Study 301 or 303 Only events that occurred in
gt 10 in either arm were analyzed for statistical
significance.
26
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

27
Study 301DSMB Interim Analysis Review

• 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

28
FTC in Treatment-naïve Patients Conclusions

• FTCddIEFV 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)

29
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
30
Emtricitabine Dose Interval Adjustment in Renal
Impairment
31
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
32
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
33
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
34
Hyperpigmentation of the Palms
35
Incidence of Hyperpigmentation in FTC-Treated
Patients by Ethnic Group
7/52
13/186
4/59
11/111
24/297
Black
(13.5)
(7.0)
(6.8)
(9.9)
(8.1)
1/136
0/24
0/193
1/329
1/353
Caucasian
(0.7)
0.3
(0.3)
0/3
0/2
0/3
0
0
Asian
2/77
0/0
1/34
3/111
3/111
Hispanic
(2.6)
(2.9)
2.7
2.7
0/18
0/0
0/5
0
0
Other
0/0
1/22
0/0
0
1/22
Mixed Race
(4.6)
(4.6)
Emtricitabine NDA filing June 2003
36
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 5.74
• 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 24557-61 2
Groark et al. J Am Acad Dermatol 1989 211032-3
3 Don et al. Ann Intern Med 1990 112-145-6 4
GlaxoWellcome Medical Information
37
Emtricitabine Virology
38
Triple NRTI ComparisonsIncidence of the M184V/I
Mutation in Patients who Experienced Virological
Failure
100
Historical Studies of ABC/3TC/ZDV
90
78
80
74
73
70
67
67
60
52
50
40
30
20
p lt 0 .02
10
0
FTC
All 3TC
CNAAB3005
CNAA3003
EPV40001 QD
EPV40001 BID
d4TABC
AZTABC

• 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 lt 0.02)

Sanne I, et al. 43rd ICAAC, Chicago, 2003, H-868.
39
Overview of Emtricitabine (FTC) in Pediatric
Program

• Nathalie Adda, MD
• Clinical Research

40
Once Daily Emtricitabine in HIV-Infected
Pediatric Patients with Other ART Agents Study
FTC-203

• Phase I/II study in ART naïve or stable
  3TC-treated pediatric patients aged 3 mo to 17 yr
  
• N82 patients (51 ART naïve 31 3TC-stable)
• FTC dosed at 6 mg/kg QD
• Median Baseline VL
  87,096 cp/mL (naïve) 50 cp/mL (exp)
• Median Baseline CD4
  724 cells/mm3 (naïve) 1072 cells/mm3 (exp)
• Results Through Week 24
• SAE 13/82
  (15)
• Grade 3/4 labs 5/82 (6)
  
• CD4 _at_ W24
• ART-naive 984
  cells/mm3
• stable 3TC 971
  cells/mm3
• PK studies demonstrated that dose of 6 mg/kg QD
  produced similar AUC as 200 mg in adults
• These results suggest that FTC in combination
  therapy is well tolerated with potent activity.

Plasma HIV-1 RNA at Week 24 (NCF)
93
84
71
63

Saez-Llorens X, et al. 10nd CROI, Boston 2003,
Poster 872, February 13, 130-330
41
An Ongoing Phase I/II Study of Once-Daily
Emtricitabine (FTC), Didanosine (ddI) and
Efavirenz (EFV) in Therapy Naïve or Minimally
Treated Pediatric Patients Study PACTG-1021

• Phase I/II study in minimally treated or naïve
  pediatric patients aged 3 to 21 yrs at 15 sites
• Two age cohorts (3-12 yrs 13-21yrs)
• N37 patients FTCddIEFV once-daily
• FTC dosed at 6 mg/kg QD ddI dosed at 240 mg/m2
  EFV adjusted for weight and age
• Median Baseline VL 47,775 copies/mL
• Median Baseline CD4 310 cells/mm3
• Results Through Week 24
• Discontinuations 7/37
  (19)
• Grade 3/4 labs 4/37 (11)
  
• ?CD4 _at_ W24 (n33) 254 cells/mm3
• PK studies at Week 2 demonstrated that FTC and
  ddI concentrations met threshold criteria
• FTCddIEFV was easily administered with good
  activity and tolerability through W24

Plasma HIV-1 RNA at Week 24
86
81
78

McKinney R, et al. Statistical report of the
Third Interim Analysis
42
An Ongoing Open Label Study of Once-Daily
Emtricitabine in combination with Other
antiretroviral Agents in HIV Pediatric Patients
FTC-211
Plasma HIV-1 RNA at Week 24

• Phase II study in ART naïve or treated pediatric
  patients aged 3 months to 17yrs at 2 sites in
  Romania
• Three age cohorts (3-24 months 7-12yrs
  13-17yrs)
• N16 patients FTCddIEFV once-daily or
  FTCd4tLPV/r
• FTC dosed at 6 mg/kg QD ddI dosed at 240 mg/m2
  EFV adjusted for weight and age or FTC dosed at 6
  mg/kg QD d4T dosed at 1mg/kg bid LPV/r dosed at
  12/3 mg/kg bid.
• Mean duration of treatment 164 days (range 55
  to 273 days) as of the safety update data cut-off
  (October 03 , 2003).
• Preliminary results through W24

86 n6/7
No Discontinuations Grade 3/4
labs 2/16 (12) ?CD4 _at_
W24 (n8) 136 cells/mm3
43
Anti-HBV Activity of Emtricitabine (FTC) in
Patients Co-Infected with HIV and Hepatitis B
Virus

• F. Raffi1, A. Snow2, K. Borroto-Esoda2, A. Shaw2,
  J. Anderson2, J. Sorbel2, J.B. Quinn2, E.
  Mondou2, and F. Rousseau2
• 1CHU de Nantes, Nantes, France 2Gilead Sciences,
  Inc., USA

44
Introduction

• Emtricitabine (FTC) is a novel nucleoside reverse
  transcriptase inhibitor (NRTI) shown to be a
  potent and selective inhibitor of HIV-1 and
  Hepatitis B Virus (HBV) replication in vitro.
• Once daily FTC has demonstrated clinical efficacy
  against HIV and activity against chronic HBV
  infection in HIV-negative patients.

F. Raffi IAS Conference, July 13-16, 2003,
Abstract 215
45
HBsAg Patient Population
FTC treated n52 patients total across studies
Comparator n22 patients total across studies
n39 patients treated 6 months
n18 patients treated 6 months
15 with HBV DNA lt4700 C/ml at entry
5 with HBV DNA lt 4700 C/ml at entry 3 on 3TC 2
on d4T
n13 Comparator-treated with detectable HBV DNA
at entry 3 on 3TC 10 on d4T
n24 FTC-treated patients with detectable HBV
DNA at entry
F. Raffi IAS Conference, July 13-16, 2003,
Abstract 215
46
Baseline Characteristics

• Emtricitabine
  Control
• (n39) (n18)
• Undetectable HBV DNA at entry (n)
  15 5
• No. patients with Entry HBV DNA gt LOD
  24 13
• Mean age (years) 35
  39
• male 92
  92
• Mean HBV DNA (log10copies/mL)
  7.7 8.8
• Mean HIV RNA (log10copies/mL)
  4.6 4.8
• Mean CD4 count (cells/mm3)
  391 325
• Mean ALT value (U/L)
  107 50
• Patients with ALT gt ULN (n)
  10 7

F. Raffi IAS Conference, July 13-16, 2003,
Abstract 215
47
HBV DNA Suppression in Patients Treated with FTC
200 mg QD
Week of Study
F. Raffi IAS Conference, July 13-16, 2003,
Abstract 215
48
Proportion of Patients with HBV DNA lt 4700
copies/ml by Study Week
24 22 20 20 17 33 33 33 33 33
FTC HBVHIV FTC HBV
F. Raffi IAS Conference, July 13-16, 2003,
Abstract 215
49
Median Log10 Change from Baseline in HBV DNA by
Study Week
Log10 HBV DNA
FTC HBVHIV FTC HBV d4T HBVHIV
24 22 20 20 17 33 33 33 33 33 10 10
10 7 7
F. Raffi IAS Conference, July 13-16, 2003,
Abstract 215
50
Proportion of Patients with HIV RNA lt 400
copies/ml by Study Week
24 24 23 22 20 13 13 13 12 9
FTC HBVHIV Control HBVHIV
F. Raffi IAS Conference, July 13-16, 2003,
Abstract 215
51
Conclusions

• FTC produced similar suppression of HBV DNA in
  patients co-infected with HIV as that observed in
  patients infected with HBV alone
• In HBVHIV co-infected patients, the safety
  profile of FTC was similar to that of control

F. Raffi IAS Conference, July 13-16, 2003,
Abstract 215
52
Future StudiesDiscussion
53
The Future TDF/FTC Fixed Dose Combination Tablet
Tenofovir and Emtricitabine fixed dose
combination Study 934 in progress TDF/FTC/EFV vs
COM/EFV Bioequivalence and stability studies in
progress
54
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?

55
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?

56
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

57
Thank you!