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Tenofovir Disoproxil Fumarate. NDA 21-356 October 3, 2001 Gilead Sciences, Inc. Foster City, CA. Gilead Consultants. Harry K. Genant, M.D. Professor of Radiology, Orthopedic Surgery and Medicine University of California, San Francisco Robert T. Schooley, M.D. - PowerPoint PPT Presentation
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1
Tenofovir Disoproxil Fumarate
NDA 21-356
October 3, 2001
Gilead Sciences, Inc.Foster City, CA
2
Gilead Consultants
Harry K. Genant, M.D.Professor of Radiology, Orthopedic Surgery and MedicineUniversity of California, San Francisco
Robert T. Schooley, M.D.Chair, Adult AIDS Clinical Trials Group (AACTG) Executive Committee Head, Division of Infectious Diseases, and Tim Gill Professor of MedicineUniversity of Colorado Health Sciences Center
Steven L. Teitelbaum, M.D.Wilma and Roswell Messing Professor of Pathology and ImmunologyWashington University, St. Louis
3
Tenofovir Disoproxil Fumarate (TDF)
Overview of Development Program Norbert Bischofberger, Ph.D.
Clinical Trial Results Jay Toole, M.D., Ph.D.
Concluding Remarks Norbert Bischofberger, Ph.D.
4
Tenofovir Disoproxil Fumarate (TDF)
• Orally bioavailable prodrug of tenofovir (PMPA)
• Nucleotide RTI
• One tablet, once daily
• Durable activity against nucleoside resistant HIV
N
NN
N
NH2
OP
OO
O
O
O
O
O
O
O
5
In Vitro Virology
• Active in vitro against recombinant HIV with
– ZDV resistance (D67N, K70R or T215Y)
– ddl resistance (L74V)
– ddC resistance (T69D)
– multinucleoside drug resistance (Q151M complex)
• Increased activity against HIV with 3TC resistance (M184V)
• Can select in vitro for the K65R mutation in RT
– 3- to 4-fold reduced in vitro susceptibility to tenofovir
6Susceptibility of Nucleoside-Resistant
HIV-1 Clinical Isolates (Virco)
0.7 0.60.7
1.7
0.1
1.0
10.0
100
3.0 2.5
M184V(n=10)
L74V(n=5)
L74V + Y115F + M184V(n=5)
Q151MComplex
(n=10)
K65R(n=8)
T69 Insertions
(n=15)
Fold
Cha
nge
from
Wild
-Typ
e
11.7
Normal Range (< 3-fold)
Resistant (> 10-fold)Intermediate Susceptibility (3-10-fold)
T215Y +other TAMs(n=20)
3.1
7
Pharmacology
• Once-daily dosing– Long intracellular half-life (10-50 hours)
– Terminal serum t½ ~17 hours
• Not a substrate, inhibitor or inducer of CYP450– No clinically significant drug interactions with EFV, IDV,
LPV/RTV (Study 909) • Renally cleared
– Clearance not affected with co-administration of 3TC or ddI (Study 909)
• Oral Bioavailability: 25% (fasted); 39% (fed)
8
Preclinical Toxicology
• No effect on mitochondrial DNA or lactate production in vitro• In vivo studies designed to identify potential target organs in
humans:– GI – Kidney
• Proximal tubular changes– Bone
• Osteomalacia associated with nephrotoxicity in juvenile monkeys at 12x human AUC
• Reversible• No radiographic evidence of bone changes in monkeys
dosed at 4x human AUC for 3 years
9
NDA Safety Database
Patients receiving 300 mga
Total 48 weeks
NDA Submission 978 154(May 1, 2001)
NDA Safety Update 978 642(August 15, 2001)
a Includes placebo-controlled studies and compassionate access (Study 908)
10
Tenofovir Disoproxil Fumarate (TDF)
Overview of Development Program Norbert Bischofberger, Ph.D.
Clinical Trial Results Jay Toole, M.D., Ph.D.
Concluding Remarks Norbert Bischofberger, Ph.D.
11
Overview
• Placebo-controlled Studies
Design Dose (qd)Study 901 Monotherapy (n=49) 75,150, 300 & 600 mg
Study 902 Intensification (n=186) 75,150 & 300 mg
Study 907 Intensification (n=550) 300 mg
• Renal and Bone Parameters• Clinical Virology
12Study 901Design
• Randomized, double-blind, placebo-controlled, dose-escalation study of TDF monotherapy
– 4 dose levels (75 mg, 150 mg, 300 mg, 600 mg/day)
– HIV RNA 10,000 copies/mL; CD4 200 cells/mm3
• 10 patients per dose level (8 TDF, 2 placebo)
• Single dose (day 1) followed by one week washout, then once-daily dosing (days 8 to 35)
• Treatment-naïve and experienced patients were enrolled
13Study 901Baseline HIV Characteristics
Placebo TDF (n=11) (n=38)
Mean CD4 (cells/mm3) 346 391
Mean HIV RNA (copies/mL) 115,593 85,351
Prior ART use 36% 68%
14Study 901HIV RNA
Placebo 75 mg 150 mg 300 mg 600 mg (n=9) (n=10) (n=8) (n=6) (n=8)
0.03 -0.33* -0.51* -1.20* -0.84*
*p<0.003
Mean Change from Baseline to Day 35 (log10 c/mL)As Treated
15Study 901
Mean Change from Baseline in HIV-1 RNAIntent to Treat
Placebo 11TDF 75 mg 12TDF 150 mg 8TDF 300 mg 8TDF 600 mg 10
9 12 7 8 9
8 12 8 8 8
9 12 8 8 9
8 11 8 7 8
9 10 8 8 8
9 10 8 7 7
8 11 8 7 4
SingleDose
Daily Dosing
OffTreatment
BL 4 8 14 21 28 35 42 63-1.5
-1.0
-0.5
0.0
0.5
Days
Mea
n lo
g 10 c
opie
s/m
L PlaceboTDF 75 mgTDF 150 mgTDF 300 mgTDF 600 mg
16Study 902Design
• Randomized, double-blind placebo-controlled study of TDF added to existing antiretroviral regimens
• Entry criteria: Stable ART 8 weeks prior to entry consisting of
4 concomitant antiretroviral agents HIV RNA 400 - 100,000 copies/mL
• Primary Efficacy Endpoint Time-weighted average change from baseline in
HIV RNA (log10 copies/mL) at week 24 (DAVG24)
17Study 902Design
Stable ART 8 weeks
randomized2:2:2:1
24 wks 48 wks
75 mg 75 mg 300 mg
150 mg 150 mg 300 mg
300 mg 300 mg 300 mg
Placebo 300 mg 300 mg
Open Label
Double-blind
n=186
18Study 902 Baseline HIV Characteristics
Mean CD4 (cells/mm3) 374
Median HIV RNA (copies/mL) 5010
Mean prior ART (years) 4.6
Baseline resistance
NNRTI 32%
PI 57%
NRTI 94%
(n=186)
19Study 902Patient Disposition
TDFPlacebo 75 mg 150 mg 300 mg
Patients who received drug 28 53 51 54
Patients discontinued (%) 7 (25%) 5 (9%) 8 (16%) 6 (11%)
Adverse events 1 (4%) 2 (4%) 5 (10%) 2 (4%)
Lost to follow up 2 (7%) 1 (2%) 2 (4%) 1 (2%)
Lack of virologic response 2 (7%) 0 0 0
Death 0 1 (2%) 0 0
Other 2 (7%) 1 (2%) 1 (2%) 3 (6%)
(0-24 weeks)
20Study 902
Patient Disposition
TDF 75 mg 150 mg 300 mg
Patients who received drug 53 51 54
Patients discontinued (%) 14 (26%) 12 (24%) 13 (24%)
Adverse events 6 (11%) 5 (10%) 5 (9%)
Lost to follow up 3 (6%) 5 (10%) 3 (6%)
Lack of virologic response 2 (4%) 0 0
Death 1 (2%) 0 0
Other 2 (4%) 2 (4%) 5 (9%)
(0-48 weeks)
21Study 902Primary Efficacy Endpoint
TDFPlacebo 75 mg 150 mg 300 mg
Intent to Treat +0.02 -0.26 -0.34 -0.58*
As Treated +0.16 -0.16 -0.32* -0.52*
*p<0.001
Mean DAVG24 (log10 copies/mL)
22Study 902
Mean Change from Baseline in HIV-1 RNAIntent to Treat
28Placebo 27 27 26 26 22 23 0 0 05375 mg 49 53 49 48 49 48 49 46 4251150 mg 48 49 49 46 44 45 42 39 3554300 mg 51 52 52 50 49 48 49 43 43
Mea
n lo
g 10 c
opie
s/m
L
Weeks
-1.2-1.0-0.8-0.6-0.4-0.20.00.20.40.60.8
BL1 2 4 8 12 16 20 24 32 40 481 2 4 8 12 16 20 24 32 40 481 2 4 8 12 16 20 24 32 40 481 2 4 8 12 16 20 24 32 40 48
Placebo75 mg150 mg300 mg
23Study 902CD4 Count
TDFPlacebo 75 mg 150 mg 300 mg (n=28) (n=53) (n=51) (n=54)
Week 24 20 18 0 -14
Week 48 N/A 10 20 11
Mean Change From Baseline (cells/mm3)Intent to Treat
24Study 902
Grade 3/4 Adverse Eventsa
TDFPlacebo 75 mg 150 mg 300
mg (n=28) (n=53) (n=51) (n=54)
Patients (%) with Events 4 (14%) 10 (19%) 9 (18%) 9 (17%)Depression 0 2 (4%) 0 3 (6%)Asthenia 1 (4%) 0 2 (4%) 0Hepatitis 1 (4%) 1 (2%) 0 0Fever 1 (4%) 1 (2%) 0 0Headache 1 (4%) 0 1 (2%) 0Pancreatitis 1 (4%) 0 0 1 (2%)Allergic reaction 0 0 0 2 (4%) Pain 0 1 (2%) 1 (2%) 0
a 1% in either group
(0-24 weeks)
25
TDF Placebo 75 mg 150 mg 300
mg (n=28) (n=53) (n=51) (n=54)
Patients (%) with Abnormality 9 (32%) 18 (34%) 16 (31%) 16 (30%)
Triglyceride elevation 4 (14%) 9 (17%) 4 (8%) 5 (9%)Creatine kinase elevation 4 (14%) 5 (9%) 4 (8%) 6 (11%)AST elevation 1 (4%) 3 (6%) 3 (6%) 4 (7%)Neutropenia 1 (4%) 3 (6%) 1 (2%) 3 (6%)ALT elevation 1 (4%) 2 (4%) 2 (4%) 1 (2%)Lipase elevation 1 (4%) 1 (2%) 2 (4%) 1 (2%)Amylase elevation 1 (4%) 2 (4%) 2 (4%) 0Hyperglycemia 0 3 (6%) 2 (4%) 0Glucosuria 0 2 (4%) 1 (2%) 0Bilirubin elevation 0 1 (2%) 1 (2%) 1 (2%)Thrombocytopenia 0 0 2 (4%) 0
Study 902Grade 3/4 Laboratory Abnormalitiesa
a 1% in any group
(0 - 24 weeks)
26Study 907Design
• Randomized, double-blind, placebo-controlled study of TDF added to existing antiretroviral regimens
• Entry criteria:
– Stable ART 8 weeks prior to entry consisting of 4 concomitant antiretroviral agents
– HIV RNA 400 - 10,000 copies/mL
• Primary efficacy endpoint
– Time-weighted average change from baseline in HIV-1 RNA (log10 copies/mL) at week 24 (DAVG24)
27Study 907 Design
Tenofovir DF 300 mg
Placebo Tenofovir DF 300 mg
Stable ART8 weeks
randomized2:1
24 wks
48 wks
48 wks
n=550
24 wks
Double-Blind
OpenLabel
28Study 907Baseline Characteristics
Placebo TDF(n=182) (n=368)
Mean age (years) 41 42
Male 88% 84%Ethnicity
Caucasian 65% 71%African-American 19% 16%Other 16% 13%
Antiretroviral Regimen Protease-containing 58% 53% NNRTI-containing 36% 43%
29Study 907Baseline HIV Characteristics
Placebo TDF
Median HIV RNA (copies/mL) 2340 2340
Mean CD4 count (cells/mm3) 447 417
Mean ART use (years) 5.3 5.5
30Study 907Virology Substudy
Primary Resistance Mutations Placebo TDF
NNRTI 52% 46%
PI 62% 57%
NRTI 94% 94%
Baseline Genotyping (n=253)
31
Placebo TDF
Patients who received drug 182 368
Patients discontinued (%) 11 (6%) 23 (6%)
Adverse event 5 (3%) 11 (3%)Lack of virologic response 1 (<1%) 0Pregnancy 1 (<1%) 1 (<1%)Lost to follow up 2 (1%) 6 (2%)Other 2 (1%) 5 (1%)
Study 907Patient Disposition
(0-24 weeks)
32Study 907
Primary Efficacy Endpoint
Placebo TDF (n=182) (n=368) p-value
-0.03 -0.61 <0.0001
Mean DAVG24 (log10 copies/mL)
Intent to Treat
33Study 907Mean Change from Baseline in HIV-1 RNA
Intent to Treat
TDF 300 mg 368Placebo 182
335170
358179
353175
354175
353173
346173
346172
HIV-1 RNAlog10 c/mL(95% CI)
Weeks 0 2 4 8 12 16 20 24
-0.8
-0.6
-0.4
-0.2
0.0
0.2
TDF 300 mg
Placebo
34Study 907Subgroup Analyses
Mean DAVG24
Placebo TDF p-valueHIV RNA <5,000 0.03 -0.59 <0.0001 5,000 -0.22 -0.67 <0.0001
CD4 <200 0.05 -0.39 <0.0001 200 -0.04 -0.64 <0.0001
Male -0.02 -0.61 <0.0001Female -0.08 -0.66 <0.0001
Caucasian -0.02 -0.60 <0.0001Non-caucasian -0.05 -0.65 <0.0001
35Study 907
Secondary Efficacy Endpoints
Placebo TDF p-value
HIV RNA 400 copies/mL 13% 45% <0.0001
HIV RNA 50 copies/mL 1% 22% <0.0001
DAVG24 CD4 (cells/mm3) -11 +13 0.0008
Intent to Treat
36Study 907
Grade 3/4 Adverse Eventsa
Placebo TDF(n=182) (n=368)
Patients (%) with events 24 (13%) 51 (14%)Diarrhea 3 (2%) 3 (<1%)
Pain 2 (1%) 3 (<1%)Hyperlipidemia 2 (1%) 2 (<1%)Nausea 2 (1%) 2 (<1%)Depression 2 (1%) 1 (<1%)Peripheral neuritis 2 (1%) 1 (<1%)Sinusitis 2 (1%) 1 (<1%)Gastrointestinal disorder 2 (1%) 0
a 1% in either group
(0-24 weeks)
37Study 907
Grade 3/4 Laboratory Abnormalitiesa
Placebo TDF(n=182) (n=368)
Patients (%) with abnormality 68 (37%) 89 (25%)Triglyceride elevation 24 (13%) 30 (8%)Creatine kinase elevation 26 (15%) 24 (7%)Amylase elevation 13 (7%) 21 (6%)Glucosuria 6 (3%) 11 (3%)AST elevation 5 (3%) 10 (3%)Hyperglycemia 8 (4%) 7 (2%)ALT elevation 3 (2%) 8 (2%)
(0-24 weeks)
a 1% in either group
Renal and Bone Parameters
39Studies 902 and 907
Integrated Safety Analysis
• Includes all patients who received 300 mg (n=687)
– As randomized (n=422)
– Following cross-over from placebo (n=191)
– Following 48 weeks of either 75 or 150 mg (n=74)
40Studies 902 and 907Integrated Safety Analysis
Number of patients 687
n 48 weeks exposure 480
n 72 weeks exposure 156
Mean (weeks) 58
Maximum (weeks) 143
41Study 907 Serum Creatinine
Grade (mg/dL) Placebo TDF
(n=182) (n=368)
1 ( 0.5 from baseline) 2 (1%) 6 (2%) 2 (2.1-3.0) 0 03 (3.1-6.0) 0 04 (>6.0) 0 0
Maximum Toxicity Grade(0-24 weeks)
42
Grade (mg/dL) TDF
(n=687)
1 ( 0.5 from baseline) 32 (5%)2 (2.1-3.0) 03 (3.1-6.0) 04 (>6.0) 0
Studies 902 & 907 Serum CreatinineMaximum Toxicity Grade
(0-143 weeks)
43Studies 902 & 907
Consecutive Visits with Grade 1 Creatinine
32
6
1 10
5
10
15
20
25
30
35
Num
ber o
f pat
ient
s
1
2 3 4Visits
44Study 907 Serum Phosphorus
Placebo TDFGrade (mg/dL) (n=182) (n=368)
1 (2.0-2.2) 10 (5%) 21 (6%)2 (1.5-1.9) 4 (2%) 23 (6%)3 (1.0-1.4) 1 (<1%) 04 (<1.0) 0 1 (<1%)
Maximum Toxicity Grade(0-24 weeks)
45Studies 902 & 907 Serum Phosphorus
TDFGrade (mg/dL) (n=687)
1 (2.0-2.2) 51 (7%)2 (1.5-1.9) 58 (8%)3 (1.0-1.4) 3 (<1%)4 (<1.0) 1 (<1%)
Maximum Toxicity Grade(0-143 weeks)
46Studies 902 & 907 Consecutive Visits Serum
Phosphate <2.0 mg/dL
62
11
10
10
20
30
40
50
60
70
Num
ber o
f pat
ient
s
1 2 3Visits
47Studies 902 & 907Bone Fracture Rate
Total Exposure No. Fracture n (patient-yrs) Fractures Ratea
Placebo (0-24 wks) 210 99 3 3.0
TDF (0-143 wks) 687 778 13 1.7
a Per 100 patient-years
48Studies 902 and 907Bone Fracture Summary
• External review of radiographs (H. Genant, M.D., UCSF)
– Fractures result of high-impact trauma
– Normal healing observed while TDF continued
• No vertebral compression fractures
• TDF fracture rate is similar to placebo
– Rate has not increased with longer exposure
49
Safety Summary
• The safety of TDF 300 mg is similar to placebo through 24 weeks
• The safety profile of TDF shows no significant change with extended dosing
50
Efficacy Summary
• TDF 300 mg monotherapy for 28 days resulted in -1.2 log10 copies/mL change from baseline
• Active in highly treatment-experienced patients
– Increases the percentage of patients with HIV RNA 400 and 50 copies/mL
– Consistent across subgroups
– Durable through 48 weeks
51Study 907Virology Substudy
Mean DAVG24 (log10 c/mL)Placebo TDF
Baseline Mutations (n=84) (n=169) p-value
M184V -0.05 -0.68 <0.0001TAM +0.03 -0.47 <0.0001NNRTI - R +0.02 -0.49 <0.0001PI - R 0.00 -0.55 <0.0001
Response by Baseline Resistance MutationsIntent to Treat
52VirologyThymidine Analog Mutations (TAMs)
• 6 RT mutations selected in patients receiving ZDV or d4T
– M41L, D67N, K70R, L210W, T215Y/F, K219E/Q/N
– Reduced clinical response to ZDV and d4T
• Also confer cross-resistance to ddI and abacavir (with M184V)
53Studies 902 & 907
Response by Number of Baseline TAMs
Mean DAVG24
Baseline Mutations Placebo TDF (n=110) (n=222) p-value
No TAMs -0.11 -0.80 <0.0001
1 or 2 TAMs -0.04 -0.66 <0.0001
3 TAMs +0.03 -0.40 <0.0001
3 TAMs with M41L or L210W +0.01 -0.21 0.0126
3 TAMs / No M41L or L210W +0.07 -0.67 <0.0001
Intent to Treat
54Studies 902 & 907
Response by Baseline Phenotypic Susceptibility
Mean DAVG24 Fold change n Placebo TDFfrom wild-type 1.0 52 - 0.05 -0.72
>1.0 and 2.0 48 +0.03 -0.57
>2.0 and 3.0 16 +0.41 -0.51
>3.0 and 4.0 9 NDa -0.46
>4.0 13 -0.22 -0.12
aNo patients in this group
Intent to Treat
55Study 907Virology Substudy
Placebo TDFMutations (n=84) (n=169)
PI-related 8% 2%
NNRTI-related 9% 5%
Nucleoside-related 24% 16%
TAMs 14% 11%
K65R 0 3%
Development of Resistance Mutations(0-24 weeks)
56
Virology Summary
• Active against common HIV resistance mutations, including most TAMs
• Low incidence of TDF resistance mutation development
57
Clinical Conclusions
• Safe and well-tolerated
• Durable antiviral activity
58
Indication
Tenofovir DF is indicated in combination with other antiretroviral agents for the treatment of HIV infection in adults.
This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in two controlled trials of 24 and 48 weeks duration in treatment experienced adults with evidence of HIV-1 viral replication despite ongoing antiretroviral therapy.
59
Tenofovir Disoproxil Fumarate (TDF)
Overview of Development Program Norbert Bischofberger, Ph.D.
Clinical Trial Results Jay Toole, M.D., Ph.D.
Concluding Remarks Norbert Bischofberger, Ph.D.
60
Indication: Study Design
• Pivotal studies (902 and 907) carried out in treatment-experienced patients– Unmet medical need– Resistance profile enables addition of TDF to
background therapy– Intensification design permits clearest assessment
of efficacy of TDF
61
Indication: Supportive Findings
• Use of TDF in treatment-naive patients supported by– Adherence – once daily dosing– Low potential for development of resistance mutations – Safety profile: No evidence of typical ART dose-
limiting toxicities
62
Study 910
• Rollover protocol from studies 901, 902 and 907 (n=575)
• Continuing to evaluate patients through December 2002– Safety– Virology– Bone Mineral Density
• Provides over 4 years of follow up for patients treated with TDF 300 mg
63
• Blinded, active-controlled, ART-naïve patients, 96 weeks, n=601
• EFV + 3TC + d4T vs. EFV + 3TC + TDF
• Bone evaluations in all patients– Bone Mineral Density (DEXA) – Bone Biomarkers
• Osteocalcin• Bone-specific alkaline phosphatase• N and C telopeptides• Vitamin D• Parathyroid hormone
Confirmatory Study 903
64
Pediatric Development
• Pediatric development program initiated following demonstration of safety in adults
• Pediatric formulation in development, available Q1 2002
• Phase I/II studies:
– Study 926: 48 week, PK, safety, efficacy (n=24) – Study 927: Single/multiple dose PK (n=30)
• Phase III study:
– 48 week placebo controlled study of TDF added to optimized background regimens
– 2nd confirmatory study
65
Conclusions
• Once daily dosing
• No clinically significant drug interactions
• Good tolerability
• Favorable resistance profile
• Durable treatment effect