TENOFOVIR DF

1
TENOFOVIR DF

• DIVISION OF ANTIVIRAL DRUG PRODUCTS ADVISORY
  COMMITTEE
• OCTOBER 3, 2001

2
Advisory Committee Issues

• Treatment indication
• Nonclinical and clinical assessment of the
  effects of Tenofovir DF on bone
• Analysis of resistance data
• Design of trials for traditional approval

3
Advisory Committee Issues

• Proposed treatment indication
• VIREADTM , in combination with other
  antiretroviral agents, is indicated for the
  treatment of HIV-infected adults. This
  indication is based on analyses of plasma HIV-1
  RNA levels and CD4 counts in two controlled
  trials of VIREADTM of 24 and 48 weeks duration in
  treatment experienced adults with evidence of
  HIV-1 replication despite ongoing antiretroviral
  therapy. At present, there are no results from
  controlled trials evaluating the effect of
  tenofovir on clinical progression of HIV.

4
Advisory Committee Issues

• Treatment indication
• Pivotal studies 902 and 907 were conducted in a
  treatment experienced adult population
• on stable ARV therapy for at least 8 weeks
• median duration of therapy of 4 - 5 years
• mean baseline viral load 3.4 log10
• mean baseline CD4 counts 410 cells/mm3
• baseline resistance mutations - NRTI(94),
  PI(58), NNRTI(40)
• Requesting AC input regarding labeled indication

5
Advisory Committee Issues

• Bone Effects
• BMD reductions/osteomalacia were observed in 3
  species
• Mechanism not fully defined
• Clinical trial data limited for BMD
• Seeking advice regarding
• implications of nonclinical and clinical bone
  data
• recommendations for additional studies
• monitoring plans

6
Advisory Committee Issues

• Virology data
• VIREADTM NDA contains more virology data than
  other NDA
• Many analyses evaluating HIV RNA response by
  baseline phenotype and genotype
• Seeking AC comments on
• clinical resistance analyses
• inclusion in product labeling

7
VIREADTM NDA

• Submitted in May 2001
• submitted under accelerated approval regulations
• for serious and life-threatening conditions
• provide meaningful therapeutic benefit over
  existing therapies
• drug has an effect on a surrogate endpoint that
  is reasonably likely to predict clinical benefit
  or on a clinical endpoint other than survival or
  irreversible morbidity
• DAVDP requires 2 adequate and well-controlled
  trials of 24 weeks duration

8
Advisory Committee Issues

• Traditional approval plans
• Continued marketing is subject to the need to
  confirm findings to establish clinical benefit
• DAVDP requires 2 studies of 48 weeks duration to
  support traditional approval
• Study 903 is being conducted in naïve subjects
  and is fully enrolled
• Compares tenofovir DF to stavudine on a
  background of lamivudine and efavirenz
• Seeking AC advice regarding design of second
  study in pediatric population

9
Advisory Committee Agenda

• 900 a.m. Gilead Presentation
• 945 a.m. FDA Presentation
• 1030 a.m. Break
• 1045 a.m. Discussion
• 1200 p.m. Lunch
• 100 p.m. Open Public Hearing
• 200 p.m. Continue Discussion and Questions to
  the Committee
• 500 p.m. Adjourn

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NDA 21-356Tenofovir Disoproxil Fumarate

• Kimberly Struble, PharmD
• Senior Regulatory Review Officer
• Division of Antiviral Drug Products

11
Presentation Outline

• NDA Submission Overview
• Efficacy Summary
• Clinical Virology Results
• Nonclinical Assessment of Bone Abnormalities -
  Jim Farrelly, Ph.D.
• Clinical Assessment of Bone Abnormalities
• Second Study for Traditional Approval
• Summary of Regulatory Issues

12
NDA Overview

• Submission Date May 1, 2001
• Proposed Dosage Tenofovir DF 300 mg once daily
• Indication Sought Treatment of HIV infection

13
NDA SubmissionFour Clinical Studies

• Supportive
• 901 Phase 2 dose finding (35 days)
• 908 Compassionate Use Safety
• Principal
• 902 and 907 Randomized, Double-blind Placebo
  Controlled (24 weeks)

14
Principal Studies 902 and 907

• Similar Study Designs
• Safety and Efficacy of TNV vs PBO when added to
  stable ARV regimen in treatment experienced
  patients
• Similar baseline characteristics
• Differences in baseline HIV RNA
• 902 Baseline HIV RNA 400-100,000 copies/mL
• 907 Baseline HIV RNA 400-10,000 copies/mL

15
Primary Efficacy Endpoint

• Primary endpoint Time weighted change in log10
  HIV RNA over 24 weeks (DAVG24)
• DAVG is an acceptable endpoint for evaluating
  virologic responses in treatment experienced
  patients, such as those enrolled in 902 and 907
• Secondary endpoints Proportion lt 400 and 50
  copies/mL

16
HIV RNA ResultsPlacebo vs Tenofovir 300 mg
17
Mean Change From Baseline HIV RNA
DAVG24 - 0.61
DAVG24 - 0.58
2
4
8
12
24
16
20
0
WEEKS
18
Proportion lt 400 and lt 50 copies/mL
Study 902
Study 907
Weeks
Weeks
19
CD4 Cell Count ResultsPlacebo vs Tenofovir 300
mg
20
CD4 Response Study 902
DAVG24 -3.6
DAVG24 -10.5
4
8
12
24
Weeks
21
CD4 Response Study 907
DAVG24 12.6
DAVG24 -10.6
Weeks
4
8
12
16
20
24
22
CD4 Response by Baseline CD4 Studies 902 and 907
23
Efficacy Summary

• Mean viral load reductions similar for 902 and
  907 (Mean DAVG 0.5 - 0.6)
• lt 400 and lt 50 copies/mL
• numerical differences 902
• statistically significant differences 907
• Modest CD4 increases in study 907
• No differences for CD4 in study 902 over 24 weeks

24
Efficacy Summary (cont.)

• Study population in 902 and 907 may not be
  optimal for observing large increases in CD4,
  given only one new drug added to stable regimen
• Addition of one new agent did not produce
  substantial increases in CD4 over time
• Further evaluations of CD4 in studies with
  different designs are needed

25
Clinical Virology Results
26
Clinical Virology

• Applicant HIV RNA response by prospectively
  defined baseline mutation subgroups
• FDA Exploratory analyses to further investigate
  HIV RNA response according to presence or absence
  of specific NRTI mutations
• Determine if specific mutations or mutational
  patterns affected response to tenofovir

27
Clinical Virology Limitations of FDA Analyses

• Large number of potential comparisons limits
  ability to test for statistical significance
• Limited of patients for some primary NRTI and
  multi-drug resistant mutations to determine
  clinical significance
• Given these limitations FDA is soliciting
  feedback on the types of exploratory analyses
  conducted and recommendations for labeling

28
Genotypic Results
29
Genotypic Results

• HIV RNA response by presence or absence of
  thymidine analogue mutations (TAMs)
• TAMs are defined as
• M41L
• D67N
• K70R
• L210W
• T215Y/F
• K219Q/E/N

30
HIV RNA Response by Baseline TAMs
Mean DAVG24 (N)
67
-0.53 (79)
67 -
-0.62 (143)
70
-0.71 (67)
70 -
-0.54 (155)
219
-0.60 (57)
219 -
-0.58 (165)
31
HIV RNA Response by Baseline TAMs
Mean DAVG24 (N)
215 -
-0.80 (116)
-0.35 (106)
215
210 -
-0.70 (176)
210
-0.17 (46)
41 -
-0.78 (141)
-0.26 (81)
41
32
Impact of 215 Mutation on HIV RNA Response
Mean DAVG24 (N)
41 or 210
-0.25 (82)
No 41 or 210
-0.70 (25)
-0.80 (116)
215 -
33
Impact of 41 or 210 Mutation on HIV RNA Response
Mean DAVG24 (N)
No 41 or 210
-0.79 (139)
-0.26 (93)
41 or 210
34
HIV RNA Response by of Baseline TAMs Mean
DAVG24 (N)
35
Other NRTI Mutations and HIV RNA Response

• L74V/I affects tenofovir efficacy
• DAVG24 -0.17 (n18)
• Rates similar regardless if 41 or 210 mutation
  present with 74 (-0.12 to -0.19)
• K65R mutation reduces susceptibility to tenofovir
  in vitro
• DAVG24 0 (N6)
• More data needed to make any definitive
  conclusions

36
Phenotypic Results
37
Phenotypic Analyses

• To determine if tenofovir or other NRTI baseline
  susceptibility affected response
• Baseline TNF susceptibility
• TNF lt 4 fold
• DAVG24 -0.61 (n91)
• TNF gt 4 fold
• DAVG24 -0.12 (N9)

38
Resistance Summary

• Genotypic data suggest potential for some cross
  resistance between tenofovir and specific NRTI
  mutations or patterns of mutations
• However too few patients expressing some primary
  NRTI or multi-drug resistant NRTI mutations to
  determine clinical significance
• No cross resistance between tenofovir and
  lamivudine

39
Resistance Summary

• 41 or 210 mutation diminished responses, whereas
  67, 70, 215 and 219 did not
• Number and types of TAMs affect tenofovir
  efficacy
• Efficacy reduced for gt 3 TAMs which include M41L
  or L210W
• K65R and L74V/I mutation may affect tenofovir
  efficacy
• Reduced susceptibility to TNF (gt 4 fold) at
  baseline diminishes tenofovir efficacy

40
Safety Summary
41
Safety Summary

• Treatment with TNF appears to be well tolerated
• Most common AEs asthenia (19), headache (14),
  diarrhea (22), nausea (20) and pharyngitis
  (18)
• GI events greater in TNF group vs PBO
• diarrhea (22 vs 17)
• flatulence (6 vs 2)
• nausea (20 vs 15)
• vomiting (12 vs 6)

42
Nonclinical Assessment of Bone Abnormalities

• James G. Farrelly, Ph.D.
• Pharmacology Supervisor

43
Toxicity in Rat and Dog Four Week Gavage Studies

• Doses up to 500 mg/kg/day in rats
• Little toxicity seen
• Doses up to 30 mg/kg/day in dogs
• Minor toxicity in kidney but no bone toxicity

44
Toxicity in Rat 42 Week Gavage Study

• Doses _at_ 0, 30, 100, 300, 1000 mg/kg/d for 42 wks
  with 13 wk recovery and a 13 week interim
  evaluation
• Bone Effects
• ? Bone mineral content and density
• ? Cortical thickness of femur
• ? Deoxypyridinoline at three highest doses
• ? Osteocalcin at the two highest doses
• ? Plasma phosphorus
• ? Urinary calcium and phosphorus
• ? PTH

45
Toxicity in Dog 42 Week Gavage Study

• Doses _at_ 0, 3, 10, and 30 mg/kg/d for 42 wks with
  13 wk recovery and a 13 week interim evaluation
• Bone Effects
• ? Bone mineral content and density
• ? Urinary N-telopeptide
• ? Urinary calcium and phosphorus
• ? Bone specific ALP
• ? 1,25-dihydroxy vitamin D3

46
Toxicity in Mouse 13 Week Gavage Study

• Range-finding study to determine the maximum
  tolerated dose for a two year carcinogenicity
  study
• Doses studied 0, 100, 300, 600 mg/kg/d
• Toxicity was seen in the kidney and duodenum
• Carcinogenicity study is still ongoing

47
Intravenous Study in Cynomolgus Monkeys

• Monkeys were dosed for 14 days by the intravenous
  route at doses up to 25 mg/kg/day with tenofovir
• No bone toxicities were seen in this study
• There were treatment findings in the kidneys

48
Rhesus Monkey Efficacy Studies

• Studies designed to assess efficacy against SIV
• Doses Studied 10 and 30 mg/kg/day
• Bone toxicities seen after 10 months dosing
• Newborn monkeys showed earlier bone toxicity when
  dosed at 30 mg/kg/day
• At 10 mg/kg/day, no bone toxicity was seen in
  newborns dosed for two years

49
Rhesus Monkey Efficacy Studies, Cont.

• Bone Toxicity
• Seen as abnormal growth plates and trabecula of
  femurs and ribs
• Also seen were bone deformities and
  displacements, rib fractures and reduced bone
  density with bone loss
• Reduction in serum phosphorus
• Elevated ALP
• Non-hyperglycemic glucosuria and proteinuria
• Serum calcium unchanged

50
Rhesus Monkey Efficacy Studies, Cont.

• It was concluded that treatment of rhesus monkeys
  at 30 mg/kg/day results in a mineralization
  defect in developing and growing cortical bone
• The defect was considered to be osteomalacia
• The defect was reversed by reducing the dose to
  10 mg/kg/day or stopping treatment

51
Reproductive Toxicology Studies

• No bone toxicity was seen in reproductive
  toxicology studies
• Rats dosed to 600 mg/kg/day
• Rabbits dosed to 300 mg/kg/day

52
Conclusions

• Tenofovir and tenofovir DF induce bone
  toxicities in three animal species consistent
  with a diagnosis of osteomalacia
• The mechanism is unknown

53
Conclusions, Cont.

• The evidence from toxicology studies in three
  species as well as from a number of in vivo and
  in vitro studies is consistent with the
  hypothesis that the bone effects are secondary to
  a negative phosphate balance associated with
  drug-related impairment of intestinal phosphate
  absorption and/or renal reabsorption of phosphate
  and not a direct effect on bone

54
Clinical Assessment of Bone Abnormalities
55
Animal Exposures in Relation to Human Exposures

• Margin of safety
• BMD reduction in rats and dogs 6-10 times higher
  than human exposures (AUC)
• Osteomalacia in monkeys 12 times higher than
  human exposures (AUC)

56
Clinical Assessment of Bone Abnormalities

• No clinically significant changes in phosphate,
  calcium, PTH or BMD observed over time
• PTH and BMD only available for a small subset of
  patients

57
Incidence of Clinical Fractures

• 5.5 in study 902
• Proportion of patients with fracture in study 902
  is higher than that seen in FDA meta-analysis of
  13 trials
• 2 (202/10166)
• Observation may be due to small sample size but
  further investigation of potential safety signal
  warranted

58
(No Transcript)
59
Clinical Assessment of Bone Abnormalities

• Review of entire non clinical and clinical safety
  and PK data, it is unlikely TNF-related fractures
  will occur over 48 weeks
• Assuming mechanism is mediated by renal phosphate
  wasting or decreases in intestinal absorption of
  phosphate
• No significant changes in renal parameters, in
  particular phosphate
• Rate of fractures does not increase over 6 month
  time intervals

60
Clinical Assessment of Bone Abnormalities

• Insufficient numbers of patients receiving
  prolonged TNF treatment and lack of control arm
  past 24 weeks
• Therefore difficult to conclude whether or not
  TNF will cause clinical fractures over time or if
  the risk will increase over time

61
Traditional Approval
62
Traditional Approval Plans

• Two studies required assessing HIV RNA over 48
  weeks
• First study Treatment Naïve Patients
• Study 903
• TNF 3TC EFV vs D4T 3TC EFV
• Second study
• proposed in treatment experienced children

63
Two - Part Hybrid (N100)
2 wks
46 wks
Endpoint DAVG2 and DAVG48
Stable ARV gt 8 weeks randomized 11
TNF
TNF
PBO
PBO
OBR wk 2

• Patient Population
• HIV RNA gt 30,000 copies/mL
• CD4 lt 20 or lt30 with OI in last 90 days
• TX Experienced with at least 1 member of
  each drug class

64
Summary of Regulatory Issues
65
Summary of Regulatory IssuesIndication

• Study population in studies 902 and 907 quite
  select
• antiretroviral experienced
• mean baseline values 3.4 log and 410 cells

66
Summary of Regulatory IssuesIndication

• Committee discussion regarding most appropriate
  indication
• For the treatment of HIV infection
• includes both treatment naïve or treatment
  experienced patients
• For the treatment of HIV infection in patients
  who have received prior antiretroviral therapy

67
Summary of Regulatory Issues Bone Abnormalities

• Non clinical bone toxicity
• Reductions in bone mineral density seen in 3
  animal species
• Exact mechanism(s) unknown but may be due to
  renal phosphate wasting or decrease in intestinal
  absorption of phosphate

68
Summary of Regulatory IssuesBone Abnormalities

• Clinical bone toxicity
• No clinically significant changes in phosphate,
  calcium , PTH or BMD observed over time
• PTH and BMD only available for a small subset of
  patients
• Rates of fractures does not increase over 6 month
  intervals
• Controlled safety data in more patients for
  longer duration needed

69
Summary of Regulatory IssuesBone Abnormalities

• Please provide your assessment of the nonclinical
  and clinical data with regard to bone effects.
• Are there additional non clinical or clinical
  studies that the applicant should conduct to
  further evaluate tenofovir associated bone
  abnormalities?

70
Summary of Regulatory IssuesClinical Virology

• Prospective and Exploratory Analyses
• Limitations of exploratory analyses include
• Limited of patients for some primary NRTI and
  multi-drug resistant mutations to determine
  clinical significance
• Large number of potential comparisons limit
  ability to conduct tests for statistical
  significance

71
Summary of Regulatory IssuesClinical Virology

• Please provide comments on the clinical
  resistance analyses conducted during the
  development of tenofovir.
• Please provide recommendations for the types of
  clinical virology analyses that should be
  conducted for future antiretroviral drug
  development and suggestions for type of
  resistance data/analyses warranting display in
  package inserts

72
Summary of Regulatory Issues Accelerated
Approval and Phase 4 Commitments

• Please provide comments on the proposed second
  study for traditional approval
• Please provide comments for other study designs
  or patient populations that should be studied as
  phase 4 commitments

73
Tenofovir Review Team

• Clinical Kimberly Struble, Pharm.D., Jeff
  Murray, M.D., M.P.H., and Bruce Schneider, M.D.
• Stats Rafia Bhore, Ph.D., and Greg Soon, Ph.D.
• Micro Nara Battula, Ph.D.
• Clin Pharm Jooran Kim, Pharm.D., and Kellie
  Reynolds, Pharm.D.
• Pharm/tox Pete Verma, Ph.D., and Jim Farrelly,
  Ph.D.
• Chemistry Rao Kambhampati, Ph.D and Steve
  Miller, Ph.D.
• Project Management Marsha Holloman, BS Pharm,
  J.D.