Transcript VIREAD™ (tenofovir disoproxil fumarate)

Introduction
Geraldine Reilly
Gilead Science
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
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 treatmentexperienced patients
Mean Steady-State Plasma Emtricitabine
Concentration Following 200 mg QD Dose
Plasma Emtricitabine Conc (µg/mL)
10
1
Plasma half-life ~ 10 hours
0.1
Mean In Vitro IC90
0.01
Mean In Vitro IC50
0.001
0
24
48
72
Time (hrs post dose)
Wang L, et al. XIV International AIDS Conference, Barcelona 2002, Poster #4546
96
120
FTC-5'-TP Conc in PBMC (pmole/106cells
Intracellular FTC-TP Concentration
Following 200 mg QD Dose¹
10
FTC-TP mean half-life ~ 39 hours
1
0.1
3TC-TP mean half-life ~ 16 hours²
0.01
0
24
48
72
Time (hrs post dose)
1Wang
2Moore
L, et al. XIV International AIDS Conference, Barcelona 2002, Poster #4546
K., et al, AIDS 1999;13:2239-50
96
120
Pharmacokinetic Considerations for Approved
and Investigational Once-daily NRTIs
Investigational Approved
Approved
QD
as QD or BID as QD or BID
Approved
as QD
Approved
as QD
50
45
40
Hours
35
30
25
20
24 hours
*
15
10
5
**
12 hours
**
0
ZDV
d4T
Indicates range where available
* Piliero, et al. 43rd ICAAC, Chicago, 2003.
ABC
Serum half-life
3TC
ddI
TDF
Intracellular half-life
** Anderson, et al. AIDS 2003; 17(15):2159-2168.
Centers for Disease Control and Prevention. MMWR Recomm Rep. 2002;51(RR-7):1-64
FTC
Forgiveness and Once-daily
Antiretroviral Therapy (ART)
BID
QD short half-life
QD long half-life
Missed Dose
Day 1
Day 2
Drug concentration
Hypothetical and not
representative of specific
ARV agents
IC90
Zone of potential replication
IC50
0
12
24
Time (hours)
36
48
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
Emtricitabine
Monotherapy Studies
Design
Study 101 Monotherapy
Patient Population
3TC and ABC naive
14-day dosing
(n=41)
Study 102 Monotherapy
10-day dosing vs
3TC
(n=81)
3TC and ABC naive
Study 101
Emtricitabine Antiviral Activity During
Short Term (14 days) Monotherapy
0.5
Mean Change
in HIV-1 RNA (log10)
25 mg bid (n = 9)
100 mg qd (n = 8)
0.0
100 mg bid (n = 8)
200 mg qd (n = 8)
–0.5
200 mg bid (n = 8)
–1.0
–1.5
-1.92 log
–2.0
0
1
2
3
4
F. Rousseau, et al. JAC(2001) 48, 507-513
5
6
7
8
Study Day
9
10
11
12
13
14
15
Study 102
Emtricitabine Antiviral Activity Compared to Lamivudine
150 mg BID in Short Term (10 Days) Monotherapy
0
3TC 150 mg bid (n=20)
FTC 25 mg qd (n=21)
FTC 100 mg qd (n=19)
FTC 200 mg qd (n=21)
–0.5
–1.0
-1.5 log
p<0.05*
-1.7 log
–1.5
–2.0
1
2
3
4
5
6
7
8
9
10
11
12
Study Day
*p<0.05 for FTC 200 mg QD compared to each of the other treatment arms
Delehanty J. et al, 6th CROI. Chicago 1999. Abstract #16
Study 102
Emtricitabine Antiviral Activity Compared to Lamivudine
150 mg BID in Short Term (10 Days) Monotherapy
0
3TC 150 mg bid (n=20)
–0.5
FTC 200 mg qd (n=21)
–1.0
-1.5 log
p<0.05*
-1.7 log
–1.5
–2.0
1
2
3
4
5
6
7
8
9
10
11
12
Study Day
*p<0.05 for FTC 200 mg QD compared to each of the other treatment arms
Delehanty J. et al, 6th CROI. Chicago 1999. Abstract #16
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 > 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)
Clinical Program Overview:
Efficacy and Safety Studies
Design
Patient Population
Treatment-Naïve Studies
ANRS 091
(MONTANA)
FTC/ddI/EFV - Open Label
(n=40)
HIV RNA >5000 copies/ml
Study 301
FTC vs d4T [+ddI/EFV]
(n=571)
HIV RNA >5000 copies/ml
ANRS 099
(Alize)
PI switch to FTC/ddI/EFV
(n=355)
HIV RNA <400 copies/ml
Study 303
3TC switch to FTC
in 3TC-stable patients
(n=440)
HIV RNA <400 copies/ml
CD4 >100 cells/mm³
CD4: no restriction
Switch Studies
CD4: no restriction
CD4: no restriction
Study 301
Study 301
Study Design
ART-naive
patients
FTC 200 mg
ddI
EFV
d4T placebo
QD
QD
QD
BID
d4T
ddI
EFV
FTC placebo
BID
QD
QD
QD
Week 48
(N = 571)
randomized
1:1, doubleblind
Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.
Week 48
Study 301
Baseline Characteristics
FTC+ddI+EFV
(n=286)
d4T+ddI+EFV
(n=285)
36
36
Male
84%
86%
Caucasian
48%
56%
Mean HIV-1 RNA (log10)
4.8
4.8
Mean CD4 count (cells/mm3)
312
324
HIV-1 RNA >100,000 (%)
41
40
Mean age (y)
Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.
Study 301
Patient Disposition at Week 48
FTC+ddI+EFV
(n=286)
d4T+ddI+EFV
(n=285)
Patients Discontinued from Study *
49 (17%)
78 (27%)
D/C due to Adverse Event*
16 (6%)
33 (12%)
Treatment Failure*
8 (3%)
22 (8%)
Other
25 (9%)
23 (8%)
LTFU
9 (3%)
12 (4%)
Request for withdrawal
5 (2%)
4 (1%)
Protocol Violation
7 (2%)
2 (<1%)
Noncompliance
2 (<1%)
3 (1%)
*p<0.05
Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.
Study 301
% Patients < 50 copies/mL
Intent to Treat (Missing = Failure)
% Patients with HIV-1 RNA < 50 copies/mL
100
80
74%
60
58%
FTC+ddI+EFV
d4T+ddI+EFV
40
p = 0.0001
20
0
BL
0
4
8
12
16
20
24
Weeks
Cahn P, et al. 10th CROI, Boston, 2003, Poster #606.
28
32
36
40
44
48
Study 301
% Patients < 50 copies/mL
As Treated (Missing = Excluded)
% Patients with HIV-1 RNA < 50 copies/mL
100
91%
84%
80
FTC+ddI+EFV
d4T+ddI+EFV
60
p<0.05
40
20
0
BL
0
4
8
12
16
20
24
Weeks
Data on file. Gilead Sciences, Inc. June 2003.
28
32
36
40
44
48
Study 301
Mean Change From Baseline in Absolute CD4+
Intent to Treat (Missing = Failure)
200
Mean Change From Baseline Absolute CD4+ Cell Count
168
160
134
120
FTC+ddI+EFV
d4T+ddI+EFV
p = <0.05
80
40
0
BL
4
8
12
16
20
24
Weeks
Data on file. Gilead Sciences, Inc. June 2003.
28
32
36
40
44
48
Study 301
Selected* Treatment-Emergent Adverse Events
Through 48 Weeks (All Grades, Regardless of Causality)
FTC + ddI + EFV
(n=286)
D4T+ddI+EFV
(n=285)
Abdominal Pain
Headache
Asthenia
14%
22%
12%
17%
25%
17%
Diarrhea**
Nausea**
Dyspepsia
Vomiting
23%
13%
8%
9%
32%
23%
12%
12%
Dizziness
Insomnia
Abnormal dreams**
25%
16%
11%
4%
6%
9%
26%
21%
19%
13%
12%
13%
Adverse Events
Neuropathy/Peripheral neuritis**
Paresthesia**
Depressive disorders
p<0.05* *
* Reported in > 3% of FTC-treated patients in Study 301 or 303
Only events that occurred in > 10% in either arm were analyzed for statistical significance.
Study 301
Selected* Treatment-Emergent Adverse Events
Through 48 Weeks (All Grades, Regardless of Causality)
FTC + ddI + EFV
(n=286)
D4T+ddI+EFV
(n=285)
Rash event
30%
33%
Rhinitis
Increased cough**
Myalgia
Arthralgia
12%
14%
6%
5%
10%
8%
3%
6%
Adverse Events
p<0.05* *
* Reported in > 3% of FTC-treated patients in Study 301 or 303
Only events that occurred in > 10% in either arm were analyzed for statistical significance.
Study 301
Treatment-Emergent Grade 3/4 Laboratory
Abnormalities* Through 48 Weeks
FTC + ddI + EFV
(n=286)
D4T+ddI+EFV
(n=285)
Percentage with Grade 3 or
Grade 4 laboratory abnormality
34%
38%
Creatinine Kinase (>4.0 x ULN)
12%
11%
AST (>5.0 x ULN)
6%
9%
ALT (>5.0 x ULN)
5%
6%
Bilirubin (>2.5 x ULN)
<1%
<1%
Number of Patients Treated
* Reported in > 1% of FTC-treated patients in Study 301 or 303
** Only events that occurred in > 10% in either arm were analyzed for statistical significance.
Study 301
Treatment-Emergent Grade 3/4 Laboratory
Abnormalities* Through 48 Weeks, Cont
FTC + ddI + EFV
(n=286)
D4T+ddI+EFV
(n=285)
Serum lipase (>2.0 x ULN)
1%
2%
Serum amylase (>2.0 x ULN)**
5%
10%
Pancreatic amylase (>2.0 x ULN)
<1%
1%
Serum Glucose (<40 or >250
mg/dL)
2%
3%
Triglycerides (>750 mg/dL)
9%
6%
Neutrophils (<750 mm3)
5%
7%
Number of Patients Treated
p<0.05* *
* Reported in > 1% of FTC-treated patients in Study 301 or 303
Only events that occurred in > 10% in either arm were analyzed for statistical significance.
Study 301
Virology
 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
Study 301
DSMB 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
FTC in Treatment-naïve
Patients: Conclusions
 FTC+ddI+EFV 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)
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
Emtricitabine:
Dose Interval Adjustment in Renal Impairment
Creatinine Clearance (mL/min)
Recommended
Dose and
Dosing Interval
 50 mL/min
30 – 49 mL/min
15 – 29 mL/min
< 15 mL/min
(including
patients
requiring
hemodialysis)*
200 mg every
24 hours
200 mg every
48 hours
200 mg every
72 hours
200 mg every
96 hours
*Hemodialysis Patients: If dosing on day of dialysis, give dose after dialysis.
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
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
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
Hyperpigmentation of the Palms
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 5.7%4
– 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; 24:557-61
2 Groark et al. J Am Acad Dermatol 1989; 21:1032-3
3 Don
et al. Ann Intern Med 1990; 112-145-6
Medical Information
4 GlaxoWellcome
Emtricitabine Virology
Triple NRTI Comparisons
Incidence 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 < 0 .02
10%
0%
FTC +
d4T+ABC
All 3TC +
AZT+ABC
CNAAB3005
CNAA3003
EPV40001 QD
EPV40001 BID
• 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 < 0.02)
Sanne I, et al. 43rd ICAAC, Chicago, 2003, #H-868.
Future Studies
Discussion
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
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?
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?
Emtriva & Viread
Summary 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
Thank you!