Tenofovir Disoproxil Fumarate

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 Medicine University 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
Medicine University of Colorado Health Sciences
Center Steven L. Teitelbaum, M.D. Wilma and
Roswell Messing Professor of Pathology and
Immunology Washington 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

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

6
Susceptibility of Nucleoside-ResistantHIV-1
Clinical Isolates (Virco)
Normal Range (lt 3-fold)
100
Intermediate Susceptibility (3-10-fold)
Resistant (gt 10-fold)
11.7
10.0
3.1
2.5
3.0
Fold Change from Wild-Type
1.7
1.0
0.7
0.7
0.6
0.1
M184V(n10)
L74V(n5)
L74V Y115F M184V(n5)
Q151MComplex(n10)
K65R(n8)
T69 Insertions(n15)
T215Y other TAMs(n20)
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 (n49) 75,150, 300 600
  mg
• Study 902 Intensification (n186) 75,150 300
  mg
• Study 907 Intensification (n550) 300 mg
• Renal and Bone Parameters
• Clinical Virology

12
Study 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

13
Study 901Baseline HIV Characteristics
Placebo TDF (n11) (n38) Mean CD4
(cells/mm3) 346 391 Mean HIV RNA
(copies/mL) 115,593 85,351 Prior ART use 36 68
14
Study 901HIV RNA
Mean Change from Baseline to Day 35 (log10
c/mL) As Treated
Placebo 75 mg 150 mg 300 mg 600 mg
(n9) (n10) (n8) (n6) (n8)
0.03 -0.33 -0.51 -1.20 -0.84
plt0.003
15
Study 901Mean Change from Baseline in HIV-1 RNA
Intent to Treat
16
Study 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)

17
Study 902Design
Open Label
Double-blind
24 wks
48 wks
300 mg
300 mg
300 mg
150 mg
150 mg
300 mg
Stable ART ? 8 weeks randomized 2221
75 mg
75 mg
300 mg
Placebo
300 mg
300 mg
n186
18
Study 902 Baseline HIV Characteristics
(n186)

• 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

19
Study 902Patient Disposition
(0-24 weeks)

• TDF
• Placebo 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)

20
Study 902Patient Disposition
(0-48 weeks)

• 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)

21
Study 902Primary Efficacy Endpoint
Mean DAVG24 (log10 copies/mL)

• TDF
• Placebo 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

plt0.001
22
Study 902Mean Change from Baseline in HIV-1 RNA
Intent to Treat
23
Study 902CD4 Count
Mean Change From Baseline (cells/mm3) Intent to
Treat
TDF Placebo 75 mg 150 mg 300 mg
(n28) (n53) (n51) (n54) Week 24 20 18
0 -14 Week 48 N/A 10 20 11
24
Study 902Grade 3/4 Adverse Eventsa
(0-24 weeks)
TDF Placebo 75 mg 150
mg 300 mg (n28) (n53) (n51)
(n54) Patients () with Events 4 (14) 10
(19) 9 (18) 9 (17) Depression 0 2 (4) 0 3
(6) Asthenia 1 (4) 0 2 (4) 0 Hepatitis 1
(4) 1 (2) 0 0 Fever 1 (4) 1
(2) 0 0 Headache 1 (4) 0 1 (2) 0 Pancreatiti
s 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
25
Study 902Grade 3/4 Laboratory Abnormalitiesa
(0 - 24 weeks)
TDF Placebo 75 mg 150 mg 300
mg (n28) (n53) (n51)
(n54) 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) 0 Hyperglycemia 0 3 (6) 2
(4) 0 Glucosuria 0 2 (4) 1 (2)
0 Bilirubin elevation 0 1 (2) 1
(2) 1 (2) Thrombocytopenia 0 0 2
(4) 0
a? 1 in any group
26
Study 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)

27
Study 907 Design
Double- Blind
Open Label
24 wks
48 wks
Tenofovir DF 300 mg
Stable ART ?8 weeks randomized 21
24 wks
48 wks
Placebo
Tenofovir DF 300 mg
n550
28
Study 907Baseline Characteristics
Placebo TDF (n182) (n368) Mean
age (years) 41 42
Male 88 84 Ethnicity Caucasian 65 71 Afri
can-American
19 16 Other 16 13 Antiretroviral
Regimen Protease-containing
58 53 NNRTI-containing 36 43
29
Study 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

30
Study 907Virology Substudy
Baseline Genotyping (n253)

• Primary Resistance Mutations Placebo TDF
• NNRTI 52 46
• PI 62 57
• NRTI 94 94

31
Study 907Patient Disposition
(0-24 weeks)

• 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 (lt1) 0
• Pregnancy 1 (lt1) 1 (lt1)
• Lost to follow up 2 (1) 6 (2)
• Other 2 (1) 5 (1)

32
Study 907 Primary Efficacy Endpoint
Intent to Treat
Mean DAVG24 (log10 copies/mL)
Placebo TDF (n182) (n368) p-value
-0.03 -0.61 lt0.0001
33
Study 907Mean Change from Baseline in HIV-1 RNA
Intent to Treat
34
Study 907Subgroup Analyses
Mean DAVG24 Placebo TDF p-value HIV
RNA lt5,000 0.03 -0.59 lt0.0001
? 5,000 -0.22 -0.67 lt0.0001 CD4 lt200
0.05 -0.39 lt0.0001 ? 200
-0.04 -0.64 lt0.0001 Male -0.02 -0.61 lt0.0001
Female -0.08 -0.66 lt0.0001 Caucasian
-0.02 -0.60 lt0.0001 Non-caucasian
-0.05 -0.65 lt0.0001
35
Study 907Secondary Efficacy Endpoints
Intent to Treat
Placebo TDF p-value HIV RNA ? 400
copies/mL 13 45 lt0.0001 HIV RNA ? 50
copies/mL 1 22 lt0.0001 DAVG24 CD4
(cells/mm3) -11 13
0.0008
36
Study 907Grade 3/4 Adverse Eventsa
(0-24 weeks)
Placebo TDF (n182) (n368) Patients ()
with events 24 (13) 51 (14) Diarrhea 3
(2) 3 (lt1) Pain 2 (1) 3 (lt1) Hyperlipidem
ia 2 (1) 2 (lt1) Nausea 2 (1) 2
(lt1) Depression 2 (1) 1 (lt1) Peripheral
neuritis 2 (1) 1 (lt1) Sinusitis 2 (1) 1
(lt1) Gastrointestinal disorder 2 (1) 0


a ? 1 in either group
37
Study 907Grade 3/4 Laboratory Abnormalitiesa
(0-24 weeks)
Placebo TDF (n182) (n368) 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)
a ? 1 in either group
38
Renal and Bone Parameters
39
Studies 902 and 907Integrated Safety Analysis

• Includes all patients who received 300 mg (n687)
• As randomized (n422)
• Following cross-over from placebo (n191)
• Following 48 weeks of either 75 or 150 mg (n74)

40
Studies 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
41
Study 907 Serum Creatinine
Maximum Toxicity Grade(0-24 weeks)
Grade (mg/dL) Placebo TDF (n182)
(n368) 1 (? 0.5 from baseline) 2 (1) 6
(2) 2 (2.1-3.0) 0 0 3 (3.1-6.0)
0 0 4 (gt6.0) 0 0
42
Studies 902 907 Serum Creatinine
Maximum Toxicity Grade(0-143 weeks)
Grade (mg/dL) TDF (n687) 1 (? 0.5 from
baseline) 32 (5) 2 (2.1-3.0) 0 3
(3.1-6.0) 0 4 (gt6.0) 0
43
Studies 902 907Consecutive Visits with Grade 1
Creatinine
35
32
30
25
20
Number of patients
15
10
6
5
1
1
0
? 1
? 2
? 3
4
Visits
44
Study 907 Serum Phosphorus
Maximum Toxicity Grade(0-24 weeks)
Placebo TDF Grade (mg/dL) (n182)
(n368) 1 (2.0-2.2) 10 (5) 21 (6) 2
(1.5-1.9) 4 (2) 23 (6) 3 (1.0-1.4) 1
(lt1) 0 4 (lt1.0) 0 1 (lt1)
45
Studies 902 907 Serum Phosphorus
Maximum Toxicity Grade(0-143 weeks)
TDF Grade (mg/dL) (n687) 1 (2.0-2.2) 51
(7) 2 (1.5-1.9) 58 (8) 3 (1.0-1.4) 3
(lt1) 4 (lt1.0) 1 (lt1)
46
Studies 902 907 Consecutive Visits Serum
Phosphate lt2.0 mg/dL
70
62
60
50
40
Number of patients
30
20
11
10
1
0
? 1
? 2
3
Visits
47
Studies 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
48
Studies 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

51
Study 907Virology Substudy
Response by Baseline Resistance MutationsIntent
to Treat
Mean DAVG24 (log10 c/mL) Placebo
TDF Baseline Mutations (n84)
(n169) p-value M184V -0.05 -0.68
lt0.0001 TAM 0.03 -0.47 lt0.0001 NNRTI -
R 0.02 -0.49 lt0.0001 PI - R
0.00 -0.55 lt0.0001
52
VirologyThymidine 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)

53
Studies 902 907Response by Number of Baseline
TAMs
Intent to Treat
Mean DAVG24 Baseline Mutations Placebo TDF
(n110) (n222) p-value No TAMs
-0.11 -0.80 lt0.0001 1 or 2 TAMs
-0.04 -0.66 lt0.0001 ? 3 TAMs
0.03 -0.40 lt0.0001 ? 3 TAMs with M41L or
L210W 0.01 -0.21 0.0126 ? 3 TAMs / No
M41L or L210W 0.07 -0.67 lt0.0001
54
Studies 902 907Response by Baseline Phenotypic
Susceptibility
Intent to Treat
Mean DAVG24 Fold change n Placebo
TDF from wild-type ? 1.0 52 - 0.05 -0.72 gt1.0
and ? 2.0 48 0.03 -0.57 gt2.0 and ? 3.0
16 0.41 -0.51 gt3.0 and ? 4.0 9
NDa -0.46 gt4.0 13 -0.22 -0.12
a No patients in this group
55
Study 907Virology Substudy
Development of Resistance Mutations(0-24 weeks)
Placebo TDF Mutations (n84) (n169) PI-rela
ted 8 2 NNRTI-related 9
5 Nucleoside-related 24 16 TAMs 14
11 K65R 0 3
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
  (n575)
• 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
Confirmatory Study 903

• Blinded, active-controlled, ART-naïve patients,
  96 weeks, n601
• 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

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 (n24)
• Study 927 Single/multiple dose PK (n30)
• 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