FDA Review Perspective

1
FDA Review Perspective Entecavir for Hepatitis
B

• Linda L. Lewis, M.D.
• Medical Officer
• Division of Antiviral Drug Products

2
Outline of Presentation

• Overview
• Efficacy
• Safety
• Virology/Resistance
• Risk-benefit assessment
• Pharmacovigilance plan
• Questions for the committee

3
Overview
4
Overview

• Current treatment for chronic HBV
• Interferon (IFN)
• Approved 1992
• Requires parenteral administration, significant
  side effect profile
• Lamivudine (LVD)
• First effective oral therapy, approved 1998
• Emergence of resistance limits effectiveness
• Adefovir (ADV)
• Approved 2002
• Known renal toxicity may limit use in some
  populations

5
Overview

• Entecavir (ETV) development program included
  diverse population
• Multi-national sites in North and South America,
  Europe, and Asia (U.S. subjects about 10)
• 25 women, mix of Asian/non-Asian (Black/African
  Americans under-represented - 2)
• Different stages of disease and treatment
  (insufficient data to review in patients with
  decompensated liver disease)

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Overview

• Key studies all compare ETV to LVD
• 022 - Nucleoside-naïve, e antigen positive, 0.5
  mg
• 027 - Nucleoside-naïve, e antigen negative, 0.5
  mg
• 026 - Persistent viremia despite LVD treatment
  (LVD-refractory), e antigen positive, 1 mg
• 014 - LVD-refractory, dose-finding Phase 2 study
• Studies 022, 027, and 026 primary endpoint
  histologic improvement in liver biopsy after 48
  weeks of treatment

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Overview

• Supportive studies in special populations
• 015 Post-liver transplant pilot study
• 038 HIV/HBV co-infected patients
• 048 Patients with decompensated liver disease,
  compares ETV to ADV, still enrolling
• No histologic endpoints used virologic,
  serologic, and biochemical endpoints

8
Efficacy Review
9
Efficacy Review

• FDA statistical review confirmed BMS primary
  efficacy analysis
• Secondary endpoint analyses were in agreement
  with BMS conclusions
• Multiple sensitivity analyses and subgroup
  analyses were performed that supported the
  primary analysis

10
Histologic Endpoints in Phase 3 ETV Studies
Primary Efficacy Endpoint
Study 022 Study 022 Study 027 Study 027 Study 026 Study 026
ETV 0.5 mg (N314) LVD 100mg (N314) ETV 0.5 mg (N296) LVD 100mg (N287) ETV 1 mg (N124) LVD 100mg (N116)
Overall histologic improvement 72 62 70 61 55 28
Fibrosis no worse 89 82 84 79 87 70
Necroinflammatory gt 2 point decrease 74 64 73 64 55 32
Ishak fibrosis score improvement 39 35 36 38 34 16
Primary analysis Only patients with evaluable
baseline biopsy included, missing/inadequate Week
48 biopsy counted as failures
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Sensitivity Analysis of Primary Endpoint
Study 022 Study 022 Study 027 Study 027 Study 026 Study 026
ETV 0.5 mg LVD 100 mg ETV 0.5 mg LVD 100 mg ETV 1 mg LVD 100 mg
Overall histologic improvement 72 62 70 61 55 28
FDA sensitivity analysis C 77 72 78 70 62 33
FDA sensitivity analysis D 64 55 64 56 48 22
C Missing/inadequate baseline or Week 48 biopsy
excluded D Includes all treated patients,
missing/inadequate Week 48 biopsy counted as
failures
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Selected Secondary Efficacy Endpoints
Study 022 Study 022 Study 027 Study 027 Study 026 Study 026
ETV 0.5 mg LVD 100 mg ETV 0.5 mg LVD 100 mg ETV 1 mg LVD 100 mg
HBV DNA PCR lt 400 copies/mL 72 42 95 77 22 1
Log HBV DNA by PCR (mean change from baseline) -7.0 -5.5 -5.2 -4.7 -5.1 -0.5
HBeAg seroconversion 21 18 NA NA 8 3
ALT normalization (lt 1 x ULN) 69 61 78 71 65 17
13
Efficacy Subgroup Analysis

• The treatment effect measured by the primary
  endpoint was comparable across the following
  strata
• Gender
• Race
• Age (by quartiles)
• Geographic region
• HBV subtype
• Baseline ALT (by quartiles)
• Baseline bDNA or PCR (by quartiles)
• Prior LVD or IFN

14
Efficacy Subgroup Analysis

• The treatment effect measured as proportion of
  patients with ALT normalization or HBV DNA by PCR
  lt 400 copies/mL at Weeks 24 or 48 was similar
  according to
• Gender
• Race
• Age (quartiles)

15
Subgroup Analyses Primary endpoint by baseline
covariates
Favors ETV
Favors LVD
16
Safety Review
17
Safety Review

• FDA clinical review confirmed general safety
  assessment of ETV
• No significant differences in rates or pattern of
  common AEs or laboratory abnormalities compared
  to LVD
• Rates of SAEs (8 both treatment groups),
  discontinuations due to AEs (1 ETV, 4 LVD), and
  deaths (lt 1 both groups) were low
• ALT flares, CNS adverse events, and malignancies
  reviewed in detail

18
Safety Review ALT Flares

• In nucleoside-naïve subjects, mean ALT values
  decreased from baseline to Week 48 in both
  treatment groups
• On-treatment ALT flares uncommon - 15/679 (2)
  ETV, 27/668 (4) LVD
• Study design allowed only patients who met
  Response criteria to discontinue treatment and be
  followed off therapy more subjects met the
  criteria in Study 027 analysis of off-treatment
  flares represents selected subjects
• Off-treatment ALT flares slightly more common
  both groups - 15/414 (4) ETV, 30/377 (8) LVD

19
Safety Review ALT Flares

• In LVD-refractory subjects, on-treatment flares
  in 4/183 (2) ETV subjects and 19/190 (10) LVD
  subjects
• Smaller proportion of LVD-refractory subjects met
  the Response criteria, discontinued therapy, and
  were followed off-treatment selected subgroup
• Off-treatment flares occurred in 3/56 (5) ETV
  subjects and 0/31 LVD subjects

20
Safety Review Nervous System Adverse Events in
Study 005

• Incidence of grouped CNS events increased with
  increasing doses, trend toward more frequent AEs
  of dizziness and insomnia with 0.5 mg

21
Safety Review On-Treatment Nervous System
Adverse Events in Pivotal Studies
Nucleoside-naive Nucleoside-naive LVD-Refractory LVD-Refractory
ETV 0.5 mg (N679) LVD 100 mg (N668) ETV 1.0 mg (N183) LVD 100 mg (N190)
Percent with any CNS AE 33 32 36 32
Anxiety 2 lt1 3 3
Dizziness 6 6 8 6
Headache 20 19 21 19
Insomnia 4 5 5 6
Migraine lt1 lt1 2 1
Paresthesia 1 1 lt1 2
Somnolence 1 2 2 2
Syncope or Syncope vasovagal lt1 lt1 1 0
Percent with Grades 2-4 CNS AEs 9 9 15 9
22
Safety Review Malignancies Reported in Clinical
Trials

• Malignancies were tracked in all clinical trials
• 37 subjects reported malignancies in ETV
  development program
• 19/1497 (1.3) ETV subjects
• 9/899 (1) LVD subjects
• From special population studies
• 3/83 receiving ETV alone
• 2/28 receiving ADV alone
• 4/849 receiving ETV LVD

23
Safety Review Malignancies Reported in Clinical
Trials

• Malignancies reported in more than one subject in
  either treatment group included in the NDA safety
  database (1497 ETV, 899 LVD)
• HCC (7 ETV subjects, 4 LVD subjects)
• Basal cell carcinoma (2 ETV subjects, 1 LVD
  subject)
• Breast cancer (1 ETV subject, 2 LVD subjects
  including one with carcinoma in situ)
• Prostate cancer (3 ETV subjects)
• Six subjects reported to have malignancies were
  known to have had previous malignancies

24
Virology/Resistance Review
25
ETV Resistance Profile Nucleoside-Naïve
Subjects (N434)

• No genotypic or phenotypic evidence of
  ETV-resistance detected among 434
  nucleoside-naive subjects analyzed at 48 weeks of
  ETV treatment (Studies 022 and 027)
• 2 subjects in Study 022 experienced confirmed
  virologic rebound but no resistance mutations
  identified
• Follow-up needed after 48 weeks to determine the
  ETV resistance pathway in naïve subjects

26
ETV Response in LVD-refractory Subjects (N189)

• LVD-refractory subjects less likely than naïve
  subjects to achieve HBV DNA lt 400 copies/mL (21
  vs 83 when data pooled)
• gt 2 log reductions in viral load and suppression
  HBV DNA lt 400 copies/mL can occur in subjects
  with LVD-resistant HBV at baseline when treated
  with 1 mg ETV
• LVD-resistance substitutions L80V, L180M, M204V
  or I can emerge in the HBV of subjects on 1 mg
  ETV by week 48.
• These substitutions often arise in the context of
  mixtures at these sites and other LVD-resistant
  mutations at baseline.

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ETV Resistance Profile LVD-refractory Subjects

• ETV-associated resistance substitutions in HBV
  polymerase
• I169, T184, S202, and/or M250
• Emerged only when LVD-resistant mutations at L180
  and/or M204 were present at baseline
• 14/189 (7.4) of evaluated LVD-refractory
  subjects treated with ETV developed resistance
  mutations at 48 weeks
• Mutations can be associated with virologic
  rebound during prolonged therapy (3/14 at Week 48)

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Cross-Resistance

• LVD-resistant HBV clinical isolates showed 3- to
  52-fold reduced susceptibility to ETV by in vitro
  assays
• HBV developing ETV-associated resistance
  substitutions in the clinical trials were
  susceptible to ADV in vitro but remained
  resistant to LVD
• ADV-resistant HBV was susceptible to ETV in vitro

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ETV Resistance Summary

• No ETV resistance has been detected in
  nucleoside-naïve subjects treated with ETV
  through 48 weeks longer term data are needed
• ETV resistant mutations can emerge on ETV
  treatment when LVD mutations are present emerge
  at a rate of lt10 at 48 weeks
• These ETV resistance mutations are associated
  with virologic rebound
• ETV is cross-resistant with LVD but not ADV by in
  vitro assays

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Risk-benefit Assessment and Pharmacovigilance Plan
31
Risk-benefit assessment

• Patients with chronic HBV have increased risk of
  HCC and probably other malignancies
• Accumulating evidence that treatment of chronic
  HBV may decrease the progression of disease
• Efficacy of ETV as measured by liver histology,
  HBV DNA, or other endpoints better or equivalent
  to that of LVD over 48 weeks of treatment
• General safety and tolerability profile of ETV
  similar to that of LVD

32
Risk-benefit assessment

• Positive carcinogenicity findings in animal
  studies are not rare and are described in
  approved product labels
• Animal carcinogenicity studies identify hazard
  signal not level of risk
• Quantifying the human cancer risk is difficult
• Mechanism of carcinogenicity is likely to be
  different for different drugs
• Risk-benefit assessment has been made on a
  case-by-case basis

33
Pharmacovigilance plan

• Increased monitoring and analysis of
  post-marketing safety reports and reporting to
  FDA
• Continued tracking of subjects in clinical trials
  (through ongoing rollover and observational
  studies)
• Proposed large simple safety study to evaluate
  occurrence of major events in broader clinical use

34
Pharmacovigilance plan Proposed post-marketing
study

• Strengths of proposed study
• Study design with randomization, active control,
  stratification by prior treatment, pertinent
  endpoints and planned analyses
• Will evaluate international population,
  real-life use, allow enrollment of patients
  with concomitant HCV and HIV and spectrum of HBV
  disease
• Size of study (12,500), enrollment through many
  local physicians each following relatively small
  number of patients

35
Pharmacovigilance plan Proposed post-marketing
study

• Potential limitations of proposed study
• Length of study may not be adequate to identify
  malignancies with long latency
• Subjects may switch from original assigned
  treatment to comparator group
• Number lost to follow-up may be higher than
  anticipated
• No specific tumor type can be targeted
• No way to stratify for all possible co-factors
  for malignancy in population

36
Pharmacovigilance plan Proposed post-marketing
study

• Study would be similar in size and scope to some
  others that have been requested by FDA or that
  have identified other risk factors
• Study might identify changes in 5-8 year risk of
  HCC or other tumors in patients receiving
  treatment for HBV
• Negative findings at the end of the study may not
  equate to a conclusion of no risk

37
Pharmacovigilance plan Animal carcinogenicity
findings in context

• Antiviral drugs with positive animal
  carcinogenicity findings risk-benefit decisions
• Zidovudine Consequences of untreated HIV,
  uninfected infants exposed perinatally followed
  in long-term outcome study (PACTG 076/219)
• Ritonavir Consequences of untreated HIV
• Ganciclovir Consequences of untreated CMV,
  boxed warning in label
• Cidofovir Consequences of untreated CMV, boxed
  warning in label
• Famciclovir Treatment for HSV, weak hazard
  signal based on animal data

38
Pharmacovigilance plan Animal carcinogenicity
findings in context

• Drugs with positive animal carcinogenicity
  findings approved for other indications
• Lipid-lowering drugs
• Anticonvulsants
• Osteoporosis
• ADHD
• Gastroesophageal reflux

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Pharmacovigilance plan

• The FDA has requested post-marketing studies to
  assess the risk of human cancer for some approved
  drugs
• Long-term prospective observational study of a
  drug compared to an appropriate control group
• Registry of patients using the drug long term
• Post-marketing surveillance program
• Retrospective cohort study to measure the
  incidence of a specific tumor and the
  contribution of a drug

40
FDA Summary

• In well-conducted clinical trials ETV was shown
  to provide superior efficacy compared to LVD in
  multiple analyses of histologic, virologic,
  biochemical, and composite endpoints
• Treatment benefit of ETV over LVD greatest in
  LVD-refractory subjects
• General safety and tolerability of ETV was
  similar to LVD in all populations studied
• Safety and tolerability profile of ETV similar in
  nucleoside-naïve and LVD-refractory subjects

41
FDA Summary

• Pre-clinical studies identified ETV as
  carcinogenic in mice and rats
• Clinical relevance of animal carcinogenicity data
  is unknown
• To date, no increase in human malignancies has
  been identified in the clinical trials
• BMS has proposed a large simple safety study
  designed to identify increased cancer risk in
  patients receiving ETV as part of their
  pharmacovigilance program

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Questions for the Committee
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Question 1

• How would you assess the risk-benefit of ETV in
  the context of the available clinical safety,
  efficacy, resistance, and non-clinical
  carcinogenicity data?

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Question 2

1. Does the risk-benefit assessment for entecavir
   support the approval of entecavir for the
   treatment of chronic HBV in adult patients?
2. If the answer to 2A is no, what information
   would be needed to support a resubmission?

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Question 3

1. If the answer to 2A is yes, discuss whether the
   results of the rodent carcinogenicity studies
   should impact the Indication and Usage section of
   the product labeling.
2. Based on the available data, discuss the
   potential role of entecavir in the HBV treatment
   armamentarium.

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Question 4

1. Assess the potential risks and benefits of
   proceeding with development of entecavir for the
   treatment of chronic HBV in pediatric patients.
2. What, if any, additional information is needed in
   order to proceed?

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Question 5

• Discuss the applicants proposed
  pharmacovigilance plan to address human cancer
  risk, including comments on the design of the
  proposed large simple study.

48
Question 6

• Are there other issues that you would like to
  see addressed through post-marketing commitments?