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GSK’s HxNx/AS03 Pandemic Influenza Vaccines

Development of an Adjuvanted H1N1 Pandemic Vaccine for the United States Presentation to the Vaccines and Related Biological Products Advisory Committee, 23 July 2009. Monovalent, vaccine strain recommended by WHO Std dose is 3.75µg HA administered twice, 21 days apart

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GSK’s HxNx/AS03 Pandemic Influenza Vaccines

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  1. Development of an Adjuvanted H1N1 Pandemic Vaccine for the United StatesPresentation to the Vaccines and Related Biological Products Advisory Committee, 23 July 2009

  2. Monovalent, vaccine strain recommended by WHO Std dose is 3.75µg HA administered twice, 21 days apart 10-dose Ag vial w/ thimerosal preservative 10-dose adjuvant vial Mixed prior to injection AS03 manufactured in Belgium, USA Ag manufactured in Dresden or Quebec (different processes) GSK’s HxNx/AS03 Pandemic Influenza Vaccines EMEA approved GSK’s Dresden H5N1/AS03 vaccineMay 2008 (also licensed in Australia, Singapore, Malaysia, Hong Kong) Also issued a “mock-up” authorization permitting rapid licensure of a similar vaccine w/ a new pandemic strain upon submission of technical & limited clinical data

  3. Quebec-H5N1/AS03: US Regulatory Framework • GSK has planned to submit a BLA for its Q-H5N1/AS03 vaccine in 2009, supported by a data package agreed with CBER in Sep 2008 • Safety and immuno data (N=3,574), in subjects 18 to 93 years of age • Supportive data from D-H5N1/AS03 studies • Safety summary in N=9,900 D/Q-H5N1/AS03 recipients, 2,400 controls • Demonstration of clinical and manufacturing consistency • Supportive pre-clinical pharmacology and toxicology data GSK believes the above data support use of H1N1/AS03 vaccine under an EUA

  4. H5N1/AS03 with Ag from Dresden or Quebec is Immunogenically Equivalent D 42 GMT Q = 465 D = 480 GMT ratio = 0.94 (0.75, 1.17) CBER criterion CBER response criterion Langley J, et al. Safety and cross-reactive immunogenicity of two H5N1 A/Indonesia/5/2005 (clade 2.1) AS03-adjuvanted prepandemic candidate influenza vaccines. A phase I/II clinical trial. ESWI 2008, Villamoura, Portugal.

  5. H5N1/AS03 is Highly Immunogenic in Children, Adults and Elderly Adults * Similar proportions observed for attainment of a HI titer ≥1:40 GSK data on file

  6. H5N1/AS03 Protects Ferrets Against Heterologous Intra-Tracheal Challenge 7.0 6.0 5.0 4.0 Log TCID50 Per g tissue 3.0 15 Ag only AS only 2.0 1.0 0.0 1.7 3.8 7.5 15 Immunizations at D0 and D21 (A/Vietnam/1194/04) Challenge at D49 (wild-type virus A/Indonesia/5/05, 105 TCID50) Results 5 days after challenge Mean Virus Titers in Lung Tissue Cross-protection against lethal H5N1 challenge in ferrets with an adjuvanted pandemic influenza vaccine. Baras B, Stittelaar KJ, Simon JH, Thoolen RJ, Mossman SP, Pistoor FH, van Amerongen G, Wettendorff MA, Hanon E, Osterhaus AD. PLoS ONE. 2008 Jan 2;3(1):e1401.

  7. H5N1/AS03 Integrated Summary of Safety (ISS): Unsolicited AEs in Adults 18 to 93 Years of Age • In 5 blinded RCTs, the occurrence of medically-attended and serious AEs was comparable between vaccine and control (table below) • Reactogenicity was increased, especially injection site pain • Predominantly mild and transient • No escalation with 2nd doses, ≥ 95% compliance with dose 2 • Mild, transient axillary discomfort, but no increase in enlarged/tender nodes GSK data on file

  8. Prospective Safety Evaluation of Flu/AS03 Vaccines is Continuous • In all of GSK’s active and planned trials for adjuvanted influenza vaccines, there is active surveillance for potentially immune-mediated diseases. • As new data are generated, they are shared with regulatory authorities • TIV/AS03 vs TIV (N=43,000,1:1) • June IDMC review of RR (adjuvanted vacc / control) for SAEs, immune-mediated events, other events of interest over 6 mos of f/u • The IDMC recommended “that the study continue as described in the protocol, including administration of a 2nd (annual) dose of study vaccine” GSK’s current safety data support a favorable risk-benefit profile for AS03-adjuvanted influenza vaccines

  9. Development Approach: D → Q H1N1 Trialsto Support Emergency Use Authorization • Near simultaneous adult and pediatric evaluations • Confirm benefit of adding AS03 to H1N1 • Ag-sparing • Superior immunogenicity vs. plain Ag • Cross-reactive immunity against drift variants • 1-visit schedule (2 doses simultaneously) • Assess interference between TIV and H1N1 (sequential or co-ad) • Can use of AS03 overcome interference? • Confirm equivalent immunogenicity (D vs Q) • Rapidly expand safety database • By Dec, N~4,500 exposed to H1N1/AS03 in RCTs

  10. Anticipated Availability of Pilot Data from Non-IND and IND Studies Aug Sep Oct Nov Dec Jan Feb Dose 1 IA Dose-2 data availability 021 adult, HPLC N=120 Post-dose 1 reactogenicity and immunogenicity data will be generated via interim analyses in non-IND studies 007 adult, SRID N=120 N=170/ 144 018/ 020 adult (TIV interference) N=200/ 200 009/ 010 6m to 17 yrs 001 adult N=1260 003 6 mos to 8 yrs N=800 019 adult (TIV interference) N=600 005 adult Q vs D-H1N1 N=600 All timings contingent on availability of clinical supplies

  11. Summary • GSK will manufacture an adjuvanted H1N1 vaccine, that based on data from the related H5N1 vaccine, is likely to be: • Highly immunogenic for children, adults and elderly adults • Antigen-sparing, time-sparing • Cross-reactive against drift viruses • Well-tolerated with a favorable risk-benefit balance • Novel approach; use would be under EUA • Pilot adult data (adjuvant vs no adjuvant) may come by mid-Oct from: • GSK–conducted study of HPLC-released vaccine • NIH-conducted study of Sanofi-Pasteur antigen/AS03 • Depending on timing of DHHS request: • AS03 delivery for use w/ S-P antigen could start end-Aug • GSK’s H1N1/AS03 vaccine delivery could start mid-Oct

  12. Thank you

  13. ISS: No Strength of Association for AESI with H5N1/AS03 vs TIV (no AS03) By Fischer’s exact test, p = 0.223 for 16 vs 1 No clear temporal patterns. p = 1.000 for 16 vs 18

  14. H5N1/AS03 Generates Better T and B Memory than H5N1 Only H5 peptide pool-specific CD4 T-cells (VN and Shared (VN-Indo) Increase (D42 – D0) in vaccine-specific B memory cells VietnamT VietnamT Shared Shared 1000 *** Day 0 *** Day 42 800 *** Frequency of specific CD4+ T-cells (dcyt+CD4+ T-cells/Mio CD4+ T-cells) 600 400 200 0 3.8 µg 3.8 µg + AS *** p<0.001: significance for adjuvant system effect Study H5N1-007, GSK data on file

  15. H5N1/AS03 Allows 1 Visit Immunization 100 96.9% 92.8% 71 .6% 72.0% 75 Seroconversion rate (%) 50 25 0 0, 21 0,14 0, 7 0, 0 HI antibody response to vaccine strain 14 days after last dose Study Q-Pan009, GSK data on file

  16. H5N1/AS03 is Antigen-Sparing: Homologous HI Antibody Responses 100 3.8µg H5 7.5µg H5 15µg H5 75 30µg H5 3.8µg H5 AS Seroconversion rate (%) 50 CBER criterion 7.5µg H5 AS 40 15µg H5 AS Adults, 18-60 years of age 30µg H5 AS 25 0 Post first dose Post second dose Leroux-Roels et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007; 370 (9587): 580–89.

  17. H5N1/AS03 Elicits Cross-Clade Immunity:Clade 1 Vaccine vs Clade 2 Strains Microneutralization Results A/Indonesia/5/05 Clade 2.1 A/turkey/Turkey/1/05 Clade 2.2 A/Anhui/1/05 Clade 2.3 100 80 60 40 Seroconversion rate (%) 20 0 3.8 µg 3.8 µg + AS 3.8 µg 3.8 µg + AS 3.8 µg + AS 3.8 µg Day 21 Day 42 20 subjects per group Day 180 Leroux-Roels et al. Broad clade 2 cross-reactive immunity induced by an adjuvanted clade 1 rH5N1 pandemic influenza vaccine. PLoS ONE 2008; 3 (2):e1665.

  18. Prime Adults 18-60 (D-PAN-H1N1-007) D.0 D.21 D.42 M.6 M.12 Timepoints : • Designed for speed = 10 weeks to generate key results • Annual registration study methodology • 15µg plain serves as • a benchmark for immunogenicity • a control for adjuvanted group • Will be pooled with next study “008” to increase immuno & safety database H1N1 3.75µg+AS03 H1N13.75µg+AS03 60 subj. BS BS BS BS BS H1N115µg plain H1N115µg plain 60 subj. BS BS BS BS BS = Blood sampling BS

  19. Children 6 - 35 Mo.(D-PAN-H1N1-009) Homologous booster 3 age strata: 6-11 months 12-23 months 24-35 months • Staggered start of 3.75/AS03 • Control group deleted after feedback from EMEA H1N1 Task Force • Interim of Primary vaccination • Aim to demonstrate boostability • Results expected not earlier than 20 weeks after start D 0 D 21 Timepoints : M 6 + 7 days M 6 M12 D 42 M6+21d Dose 1 Dose 2 Boost Half Dose ~100 subj. BS BS BS BS BS BS Boost Dose 2 Dose 1 Full Dose BS ~100 subj. BS BS BS BS BS = Blood sampling BS

  20. Children 3 - 17 yrs (D-PAN-H1N1-010) Homologous boost • Uses full “adult” dose from 3 yrs to 17 yrs incl. • Control group deleted after feedback from EMEA H1N1 Task Force • Interim of Primary vaccination • Aim to demonstrate boostability • Results expected not earlier than 20 weeks after start D 0 D 21 M 6+21d M 6+7d D 42 M 6 M12 Timepoints : Boost Dose 1 Dose 2 Full Dose BS BS BS BS BS ~200 subj. = Blood sampling BS 2 age strata: 3 – 9 years10 – 17 years

  21. D-PAN-H1N1-001 (establish dose/formulation)SS 22-Sep-09 Evaluates A/California vaccine adjuvanted and unadjuvanted dosing regimens in adults ≥18 yrs Primary Objectives = CBER (CHMP) criteria for Group A 18-64 (60) and 65+ (60+) years old Randomized, observer-blind, age stratified 2:1:1:4:4, 18-40, 41-51, 52-64, 65-74, and ≥75 yrs Safety and immunogenicity Days 0 (screening), 21, 42, 182. Group C will receive 2 doses of 3.75 g/AS03A on Day 0, one dose in each arm. To maintain blind, Group D will receive 30 g in one arm and placebo in the other arm on Day 0.

  22. D-PAN-H1N1-003 (establish dose in 6 mo - <9 yrs)SS 22-Sep-09 Evaluates A/California vaccine adjuvanted and unadjuvanted dosing regimens in children 6 months to <9 years of age. Primary Objective = meet or exceed CHMP/CBER criteria set for adults 18-64 Randomized, observer-blind, age stratified 1:1, 6<36 months and 3<9 years Safety and immunogenicity Screening, Days 21, 42, 182. Children 9 to <18 years will be excluded from this trial; their safety and immuno profile will be approximated from young adults 18-40 in D-001 and children 3 to <9 years here. They will be included in the expanded safety trial Q-PAN H1N1-004.

  23. Q-PAN-H1N1-005 (rapid bridging study in adults)SS 22-Oct-09 Will provide first Q-Pan data Study start as soon as both vaccines available. Rapid enrollment. Primary immuno objectives will be based on meeting or exceeding CBER and CHMP HI criteria for subjects in Groups A and B with secondary objectives to evaluate the immunogenicity of other vaccine formulations against CBER criteria and assess equivalence of D and Q Ag. Randomized, observer-blind, age stratified 2:1:1, 18-40, 41-51, and 52-64 yrs of age Safety and serology Days 0 (screening), 14, 28 (primary immuno endpoints), 182

  24. D-PAN-H1N1-019 (sequential and Co-Ad TIV)SS 22-Sep-09 • Primary objective: to demonstrate the non-inferiority of the immune response to H1N1v virus for sequential and co-administration of seasonal and pandemic vaccines as compared to subjects who receive only pandemic plain antigen vaccine. • Subjects will be randomized by site (age 18 to 35 years of age) • Secondary objectives include: • Effect of TIV pretreatment and TIV co-administration on adjuvanted H1N1v immune responses • Comparison of immune responses to H1N1v following TIV pretreatment for adjuvanted vs unadjuvanted H1N1v vaccines • Effects of H1N1v vaccination on TIV immune responses • Assessing whether each group meets or exceeds CBER/CHMP criteria

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