FDA/CBER VRBPAC Meeting

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• FDA/CBER VRBPAC Meeting
• February 27, 2007 Gaithersburg, MD
• NIAID H5N1 Vaccine Clinical Research Program
  Overview
• and
• Protocol 04-063 Study Results
• Linda C. Lambert, Ph.D.
• Division of Microbiology and Infectious Diseases
• National Institute of Allergy and Infectious
  Diseases
• NIH/DHHS

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NIAID
To serve public health by conducting and
supporting research on infectious and allergic
diseases

• DHHS Pandemic Influenza Research Plan
• NIAID - research on control, prevention, and
  treatment of seasonal and pandemic influenza
• Assess basic biology, immunology, host response
• Characterize newly emerging strains, molecular
  basis of virulence/transmission
• Develop and clinically evaluate of new
  diagnostics, drugs, and vaccines
  coordinate/collaborate with DHHS, NVPO, FDA, CDC
  and other Public Health Service efforts
• Generate information to further inform ongoing
  global pandemic preparedness efforts

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(No Transcript)
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NIAID H5N1 Vaccine Clinical Research Program
Objectives I

• Obtain H5N1 vaccine from manufactures with
  licensed products as quickly as possible
• May 2004 award contracts to Aventis Pasteur
  (sanofi pasteur)
• Produce a pilot-scale lot of H5N1 vaccine using
  scaled-down processes similar to those for their
  licensed vaccines
• 2 formulations 30 mcg/ml, 90 mcg/ml
• Gain experience overcoming technical and
  logistical issues - USG and sanofi pasteur
• Demonstrate use of reverse genetics to generate
  H5 vaccine reference viruses and obtain USDA
  Select Agent exemption
• Produce reagents to measure vaccine potency
• Develop assay capacity to measure vaccine
  responses
• Prepare for commercial-scale manufacturing

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NIAID H5N1 Vaccine Clinical Research Program
Objectives II

• Rapidly implement well controlled Phase I/II
  clinical trials to obtain data on the safety and
  immunogenicity of the vaccine
• Provide initial data on the comparative
  dose-ranging immune responses to form the basis
  of additional clinical trials
• Assess multiple study populations adults,
  elderly, and pediatric populations
• Support H5N1 hemagglutinin (HI) and
  microneutralization (MN) immunoassays, data
  collection/analysis

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NIAID H5N1 Vaccine Clinical Research Program
sanofi pasteur

• June 2004 NIAID provided clade 1 H5N1 reference
  virus to sanofi pasteur
• rgA/Vietnam/1203/2004 with neuraminidase (NA)
  and genetically modified hemagglutinin (HA) gene
  6 PR8 genes
• March 2005 sanofi pasteur delivered vaccine
• April 2005 NIAID initiated H5N1 vaccine trial in
  adults
• 3 VTEU sites fully enrolled May 20th
• NIAID transfers preliminary and final data sets
  for 04-063 to sanofi pasteur for BLA submission
• John Treanor results adult study (NIAID
  Protocol 04-063 published NEJM 3/2006) and
  brief overview of follow-on studies

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NIAID evaluation of sanofi subvirion inactivated
rgA/Vietnam/1203/04 x PR8 H5N1 Vaccine
Presentation to the FDA VRBPAC Meeting 27
February 2007
J. Treanor, J. Campbell, and K. Zangwill for the
DMID 04-063 study team
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NIAID approach to evaluation of sanofi subvirion
H5N1 vaccine
Protocol 04-063
Protocol 04-076
Protocol 04-077
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04-063 sanofi subvirion inactivated H5N1
vaccine in healthy adults

• Published data up to and including day 56 (NEJM
  354 (13) 1343-51, March 30, 2006)
• Healthy adults ages 18 to 64
• Prospective, multicenter, randomized, double
  blind clinical trial
• Interventions dose ranging, two IM doses of H5
  vaccine or placebo separated by 28 days
• 7.5 mcg, 15 mcg, 45 mcg, 90 mcg, (n100/group)
• Endpoints
• Safety solicited and unsolicited AEs
• Co-primary Immunogenicity neutralizing and HAI
  antibody
• Determined proportion achieving titer of gt 140
  28 days after 2nd dose
• Correlation of either assay with protection
  against H5N1 infection or disease is unknown

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Demographics of enrolled subjects Protocol
04-063
Demographics of enrolled subjects Demographics of enrolled subjects Demographics of enrolled subjects Demographics of enrolled subjects Demographics of enrolled subjects Demographics of enrolled subjects
Number of subjects () in the following dose groups Number of subjects () in the following dose groups Number of subjects () in the following dose groups Number of subjects () in the following dose groups Number of subjects () in the following dose groups
Characteristic Placebo (n48) 7.5 mcg (n101) 15 mcg (n101) 45 mcg (n98) 90 mcg (n103)
White 39 (81.3) 81 (80.2) 78 (77.2) 75 (76.5) 84 (81.6)
Black 3 (6.3) 5 (5.0) 6 (5.9) 12 (12.2) 11 (10.7)
Asian 4 (8.3) 13 (12.9) 13 (12.9) 10 (10.2) 8 (7.8)
Pacific Islander 0 (0.0) 0 (0.0) 1 (1.0) 0 (0.0) 0 (0.0)
Multiracial 2 (4.2) 2 (2.0) 2 (2.0) 1 (1.0) 0 (0.0)
Hispanic 4 (8.3) 13 (12.9) 11 (10.9) 6 (6.1) 13 (12.6)
Female 22 (45.8) 51 (50.5) 65 (64.4) 42 (42.9) 55 (53.4)
Previous vaccine 20 (41.7) 39 (38.6) 42 (41.6) 42 (42.9) 44 (42.7)
Age (median, range) 38 (21-62) 39 (18-64) 40 (22-64) 38 (19-63) 38 (18-64)
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Summary of safety, Protocol 04-063

• Dose-related pain and tenderness at injection
  site (0 severe, 7 moderate, 53 mild at 90 mcg,
  dose 1)
• Rates are similar after dose 1 and dose 2
• No difference in rates of systemic side effects
  between any dose and placebo
• 1 SAE not related to vaccine occurred within 56
  days of dose 1

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Reverse cumulative distribution of MN antibody at
day 56 (28 days after dose 2)
54 (43,64)
Percent at or above indicated titer
NEJM 3541343-51, 2006
Reciprocal titer
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Reverse cumulative distribution of HAI antibody
at day 56 (28 days after dose 2)
58 (47, 67)
Percent at or above indicated titer
NEJM 3541343-51, 2006
Reciprocal titer
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Protocol 04-063 reanalysis

• Changes in analysis were suggested after study
  completion and publication (March 06) based on
  FDA guidance document (March 06) and discussions
  with FDA (April 21, 2006).
• HAI became primary focus of immunogenicity
  evaluation.
• FDA recommended redefining the value assigned for
  the first dilution from 120 (as published) to
  110
• HAI seroresponse redefined with FDA consultation
  as requiring 1 four-fold increase over baseline
  and 2 titer of 140 or greater.
• Reanalysis involves recalculations using 110
  definition of the starting dilution, and reduces
  all reported titers by one dilution.
• No retesting of sera was performed. Only
  recalculations of results based on new
  definitions were done.

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Reverse cumulative distribution of HAI antibody
at day 56 (28 days after dose 2)
FIRST WELL dilution defined as 120
58 (47, 67)
Percent at above indicated titer
NEJM 3541343-51, 2006
Reciprocal HAI titer
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Reverse cumulative distribution of HAI antibody
at day 56 (28 days after dose 2)
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Current cumulative experience with sanofi vaccine
at 90 mcg
Number of subjects receiving one, two, or three
90 mcg doses of sanofi vaccine
Studies Randomized trials 04-063/05-090
04-076 Open label studies 05-0043 05-0129
05-0130 Total 90 mcg recipients
Populations Healthy adults Elderly
adults Previous rH5 Manufacturers Lab workers
One 103 105 37 83 35 363
Two 99 94 - 76 35 304
Three 86 80 - - - 166
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NIAID evaluation of 90 mcg dose in open label
populations safety

• Protocols 05-043, 05-129, 05-0130
• No SAE related to vaccine to date
• Rates of local and systemic solicited adverse
  events are similar to rates at 90 mcg in Protocol
  04-063

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NIAID controlled evaluation of sanofi H5N1
vaccine in additional populations

• Elderly adults (N259)
• Children 2-9 years old (45 mcg, N125)
• Database is not locked and only aggregate
  analysis available
• No vaccine related serious adverse events
• Local and systemic reactogenicity mostly reported
  as mild or moderate, rarely (1 or less) reported
  as severe