U.S. Food and Drug Administration

1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. FluBlok®Protein Sciences CorporationPresentation

3. FluBlok Recombinant hemagglutinin

4. Proposed Indication FluBlok is a recombinant hemagglutinin influenza vaccine indicated for active immunization of adults 18 years of age and older against seasonal influenza disease caused by influenza virus subtypes A and type B represented in the vaccine

5. Seasonal Influenza Highly contagious, acute viral respiratory disease occurring seasonally and globally Epidemics occur annually Results in more than 220,000 hospitalizations and on average 36,000 deaths annually in the United States Over 90% of influenza related deaths occur in people aged 65 and older Children under 5 and pregnant women in their 3rd trimester are at higher risk for severe complications [Glezen, 1982]; [MMWR, 2008]

6. Licensed Influenza Vaccine Trivalent vaccine: 2 A strains and 1 B strain Protection correlates with hemagglutinin (HA) antibodies PRODUCTION PROCESS Infect Chicken Embryos Isolation of Virus Kill Virus Isolate Virus Proteins

7. Licensed Influenza Vaccine Disadvantages Long production cycle One egg ≈ one dose Production issues possible with avian influenza outbreaks Adaptation of seed virus required Less effective in the elderly Egg allergies

8. FluBlok Composition Trivalent, seasonal influenza vaccine with 3 full-length recombinant hemagglutinin (rHA) proteins Single dose, 135 µg rHA, 45 µg each strain Produced in expresSF+® (SF+) cells without serum using a viral vector (baculovirus) Formulated without adjuvant, antibiotics or preservative Protein based vaccine with low endotoxin content

9. FluBlok:rHA produced in expresSF+ cells Baculovirus Expression Vector System (BEVS) • Engineer baculovirus with the gene of interest (e.g. hemagglutinin) • Baculoviruses highly specific to SF+ cells • Powerful promoter generates high yield of protein of interest • Purified protein • Formulate with PBS • Culture SF+ cells in fermenter • Infect SF+ cells with engineered virus • Incubate for ~48 - 72 hours

10. FluBlok Potential Advantages Vaccine composition not constrained by selection or adaptation of the influenza seed virus Cloning, expression and manufacture of FluBlok withinjust 2 months FluBlok produced in cell culture and does not utilize embryonated chicken eggs Manufacturing of FluBlok does not require biocontainment facilities High yield process allowing increased HA content to enhance immunogenicity

11. FluBlok: Potential Advantages Development Time Receipt of virus Plaque isolation Product release Freeze virus bank Start manufacturing Development time for rHA vaccine Day 0 6 30 45 75 Product release testing, i.e.: - Mycoplasma/spiroplasma: 30 days - Sterility: 14 days - General safety testing: 7days - SRID assay Start commercial production

12. Clinical Development Timeline PSC01 PSC04 & PSC06 PSC03 FDA VRBPAC 2004/05 2006/07 2007/08 2009 1993 Initiation of FluBlok Clinical Studies 9 studies performed in collaboration with NIAID BLA SubmittedApril 2008

13. FluBlokProtein Sciences CorporationPresentation

14. FluBlok Clinical Development Program BLA Studies Supporting Licensuren=3384 (3233) PSC04 2007-2008 PSC06 2007-2008 PSC03 2006-2007 PSC01 2004-2005 Non-Inferiority Immunogenicity and Safety Healthy Adults ≥65 Active Controlled Study (Fluzone®) Field Efficacy and Safety Study in Healthy Adults ≥18 to 49 yrs Placebo Controlled Non-Inferiority Immunogenicity and Safety in Healthy Adults 50 to 64 yrs Active Controlled Study (Fluzone®) Efficacy and Safety Study in Healthy Adults ≥18 to 49 yrs Placebo Controlled and Two Dose Levels of FluBlok n = number of subjects vaccinated with FluBlok ( ) = number of subjects receiving commercial formulation of FluBlok

15. Summary of Clinical Trials of FluBlok Outcome criteria to support licensure Non-inferiority criteria X X Age Group (yrs) 18-49 18-49 50-64 ≥ 65 Serologic criteria X X X X Protective efficacy X X Study PSC04 PSC01 PSC06 PSC03 Comparisons FluBlok and placebo FluBlok and placebo FluBlok and TIV FluBlok and TIV

16. Clinical Studies Supporting LicensurePSC01, PSC03, PSC04 and PSC06 Unless specified otherwise, all four trials were: Randomized Modified double blind design (i.e. all subjects, site staff, and laboratory personnel blinded, except for vaccinators) Multicenter Studies, all conducted in US Included healthy adults age 18-64 yrs or elderly adults age ≥65 yrs with medically stable underlying conditions

17. Clinical Studies Supporting Licensure PSC01, PSC03, PSC04 and PSC06 cont. SAFETY Utilized a standardized Memory Aid for solicited AEs Collected unsolicited AEs through Day 28 Final safety follow-up at Day ~180 Standardized definitions/MedDRA coding IMMUNOGENICITY Utilized a validated hemagglutinin inhibition (HI) antibody assay at a single central laboratory Utilized serological endpoint criteria specified in FDA’s May 2007 Guidance

18. PSC04 Evaluation of the Immunogenicity, Safety, Reactogenicity, Efficacy, Effectiveness and Lot Consistency of FluBlok Trivalent Recombinant Baculovirus-Expressed Hemagglutinin Influenza Vaccine in Healthy Adults Age 18 to 49 Years

19. PSC04: Design • A clinical efficacy study conducted during the 2007-2008 influenza season in which 4648 healthy adults age 18-49 years were randomized to receive either a single dose of FluBlok or saline placebo • Objectives of this study were to assess safety, lot consistency, efficacy and the immunogenicity of FluBlok

20. PSC04: Vaccine and Distribution • 2344 subjects received FluBlok – single dose: 45µg of three rHAs (135µg total) • A/Solomon Islands/3/06 (H1N1) • A/Wisconsin/67/05 (H3N2) • B/Malaysia/2506/04 (B/Victoria) • 2304 subjects received saline placebo

21. PSC04: Demographics • Age Group 18-49 • Mean Age - 33 • M/F % - 41/59 • Race/Ethnicity • White/Caucasian 67% • Black/African-American 18% • Latino/Hispanic 11% • Asian 3% • American Indian/Alaska Native <1% • Native Hawaiian/Pacific Islander <1% • Other 1%

22. PSC04: Seroconversion Seroconversion defined as (a) ≥4-fold increase in HI titer on Day 28 in subjects with a pre-vaccination titer of ≥10, with a minimum Day 28 titer of 40; or (b) an HI titer of ≥40 on Day 28 in subjects with a pre-vaccination titer <10 FDA’s May 2007 Seasonal Influenza Guidance Document specifies, for adults <65 years of age, that the lower bound of the 2-sided 95% CI should meet or exceed 40%

23. 2-sided 95% Confidence Intervals represented as error bars

24. PSC04: Seroprotection Seroprotection is defined as a post-vaccination (Day 28) HI titer of ≥40 in the FDA May 2007 Guidance Document The FDA’s May 2007 Guidance Document specifies that the lower bound of the 2-sided 95% CI of the seroprotection rate should meet or exceed 70% in adults <65 years of age

27. PSC04: Primary Efficacy Endpoint • Development of CDC-ILI with a positive NS/TS culture for an influenza virus strain antigenically resembling a strain represented in FluBlok obtained during the acute illness episode • CDC-ILI is defined as fever of 100°F or more accompanied by coughing, sore throat, or both on the same day or on consecutive days • Antigenic relatedness screened for by reciprocal HI testing using ferret antisera

28. PSC04: Sample Size • The sample size chosen for this study was 4318 randomized 1:1 (FluBlok=2159, placebo= 2159) • Assumptions: VE = 70%; Attack rate = 3% • This test has approximately 80% power with  = .05 to achieve its goal assuming a total sample size of 4318 accounting for a 5% attrition rate (post-attrition samples sizes of at least: FluBlok=2051, placebo= 2051)

29. PSC04 : 2007-08 Influenza Season • Suboptimal match between the vaccine strains and circulating strains • CDC’s Influenza Activity Website: • 77%, 33%, and 98%, respectively, of all A/H3N2, A/H1N1 and B isolates characterized during the 2007-08 season were antigenically dissimilar to the 2007-08 vaccine strains • In particular, predominant circulating B strain was of a different lineage (B/Yamagata) than represented in the vaccine (B/Victoria)

30. PSC04: Clinical Efficacy Primary Endpoint

31. PSC04: Clinical Efficacy Virus Isolates

32. PSC04: Pre-specified Exploratory Endpoints • Development of CDC-ILI with a positive NS/TS culture for any influenza virus strain obtained during the acute illness episode • Development of CDC-ILI during the surveillance period regardless of culture results

33. PSC04: Clinical Efficacy Pre-specified Exploratory Endpoints

34. PSC04: Clinical Efficacy Against any Influenza Strain – Exploratory Endpoints

35. PSC04: Clinical Efficacy Against any Influenza Strain – Exploratory Endpoints (2)

36. Vaccine Efficacy in other Studies 1 Reduction in culture confirmed influenza

38. *Fever defined as >100.4°F in this study

39. PSC04: Additional Safety Data • Unsolicited AEs • Reported in 17% of FluBlok and 17% of placebo recipients • Headache, URI most commonly reported • No notable imbalances between study groups • One case of Bell’s palsy reported in the FluBlok group • Onset within one hour of vaccination in subject with prior history • Classified by the investigator as “not related” • No adverse outcomes in 20 pregnancies in the FluBlok group • Nine subjects withdrew as consequence of AEs (5 FluBlok, 4 placebo); 7 due to pregnancy

40. PSC04: Additional Safety Data • Serious Adverse Events (SAEs) • 85 SAEs reported in 64 subjects (1.4%) • 41 in 30 FluBlok recipients (1.3%) • 44 in 34 placebo recipients (1.5%) • 84 of 85 SAEs considered unrelated, including two deaths (FluBlok-pulmonary embolism; placebo-MVA) • One “possibly related” SAE in a FluBlok recipient: • 47-year-old male hospitalized 11 days post-vaccination for pericardial and pleural effusions • Work-up did not disclose a cause • Discharged 13 days after admission (Day 24 post vaccination) • Considered as “fully recovered” at last follow-up

41. PSC01 Evaluation of the Immunogenicity and Safety of Two Preparations of Trivalent Recombinant Baculovirus-Expressed Hemagglutinin Influenza Vaccine Administered Intramuscularly in Healthy Adults Age 18-49 Years Results published: Treanor JJ et al. JAMA 297: 1577-82. 2007.

42. PSC01: Design Phase 2/3 field study during 2004-05 in 458 healthy adults 18 to 49 years of age; no high-risk groups; no previous influenza vaccination for that season Objectives were to evaluate the dose-related safety and immunogenicity of two dose levels of FluBlok Participants followed during influenza season to evaluate protective efficacy

43. PSC01: Vaccine & Subject Distribution • Participants randomized to receive either a single dose of rHA at 135µg (45µg each strain), 75µg (15µg of H1 & B and 45µg of H3), or saline placebo • A/New Caledonia/20/99 (H1N1) • A/Wyoming/3/03 (H3N2) • B/Jiangsu/10/03(B/Yamagata) • 153 subjects received 135µg rHA • 151 subjects received 75µg rHA • 154 subjects received saline placebo

44. PSC01: Demographics • Age group 18-49 • Mean Age - 31 • M/F % - 37/63 • Race/Ethnicity • White/Caucasian 85% • Black/African-American 6% • Latino/Hispanic 3% • Asian 3% • American Indian/Alaska Native 1% • Native Hawaiian/Pacific Islander 1% • Other 2%

45. PSC01: Seroconversion Seroconversion defined as (a) ≥4-fold increase in HI titer on Day 28 in subjects with a pre-vaccination titer of ≥10, with a minimum Day 28 titer of 40; or (b) an HI titer of ≥40 on Day 28 in subjects with a pre-vaccination titer <10 FDA’s May 2007 Seasonal Influenza Guidance Document specifies, for adults <65 years of age, that the lower bound of the 2-sided 95% CI should meet or exceed 40%

46. PSC01:Seroconversion Draft FDA Seasonal Influenza Guidance document posted in 2006, after PSC01 was completed. Serum dilution series used in HI antibody assay in PSC01 did not allow direct analysis of data using FDA specified criteria. Data is presented for titers exceeding 64 or 32 (post-hoc).

49. PSC01: Seroprotection Post Vaccination Titer ≥64 Seroprotection is defined as a post-vaccination (Day 28) HI titer of ≥40 in the FDA May 2007 (Draft 2006) Guidance Document The FDA’s May 2007 Guidance Document specifies that the lower bound of the 2-sided 95% CI of the seroprotection rate should meet or exceed 70% in adults <65 years of age