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 It was current when produced, but is no longer maintained and may be outdated.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 Corporation Presentation Introduction Manon Cox, PhD, MBA Chief Operating Officer Protein Sciences Corporation Efficacy Immunogenicity Safety John Treanor, MD Principal Investigator University of Rochester Summary Benefit/Risk Conclusion Manon Cox, PhD, MBA Chief Operating Officer Protein Sciences Corporation

3 FluBlok Recombinant hemagglutinin Product Recombinant hemagglutinin vaccine Dose: 135µg rHA (45µg/rHA) No adjuvant for FluBlok ProcessCell Culture (Baculovirus) Features Purified protein: high dose is feasible, no egg protein & low endotoxin content Short production cycle: no handling live influenza viruses or eggs

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

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

10 FluBlok Potential Advantages  Vaccine composition not constrained by selection or adaptation of the influenza seed virus  Cloning, expression and manufacture of FluBlok within just 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 Day Development time for rHA vaccine Plaque isolation Freeze virus bank Start manufacturing Start commercial production Product release testing, i.e.: - Mycoplasma/spiroplasma: 30 days - Sterility: 14 days - General safety testing: 7days - SRID assay Product release

/ / / FDA VRBPAC Clinical Development Timeline PSC04 & PSC06 BLA Submitted April 2008 PSC01 PSC Initiation of FluBlok Clinical Studies 9 studies performed in collaboration with NIAID

13 FluBlok Protein Sciences Corporation Presentation Introduction Manon Cox, PhD, MBA Chief Operating Officer Protein Sciences Corporation Efficacy Immunogenicity Safety John Treanor, MD Principal Investigator University of Rochester Summary Benefit/Risk Conclusion Manon Cox, PhD, MBA Chief Operating Officer Protein Sciences Corporation

14 FluBlok Clinical Development Program n =number of subjects vaccinated with FluBlok ( ) =number of subjects receiving commercial formulation of FluBlok Efficacy and Safety Study in Healthy Adults ≥18 to 49 yrs Placebo Controlled and Two Dose Levels of FluBlok BLA Studies Supporting Licensure n=3384 (3233) PSC PSC PSC PSC 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 ® )

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

16 Clinical Studies Supporting Licensure PSC01, 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 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

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 18

PSC04: Design  A clinical efficacy study conducted during the influenza season in which 4648 healthy adults age 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 19

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 20

PSC04: Demographics  Age Group  Mean Age - 33  M/F % - 41/59  Race/Ethnicity –White/Caucasian67% –Black/African-American18% –Latino/Hispanic11% –Asian3% –American Indian/Alaska Native<1% –Native Hawaiian/Pacific Islander<1% –Other1% 21

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

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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 27

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) 28

PSC04 : 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 season were antigenically dissimilar to the vaccine strains  In particular, predominant circulating B strain was of a different lineage (B/Yamagata) than represented in the vaccine (B/Victoria) 29

PSC04: Clinical Efficacy Primary Endpoint FluBlok 135µg N=2344 Placebo N=2304 Summary of virus isolation results Subjects from whom NS/TS was obtained, n (%) 273 (11.6)309 (13.4) Subjects with positive cultures, n (%) 64 (2.7)114 (4.9) Number of isolates that antigenically resembled the strains represented in the vaccine B/Malaysia/2506/2004-like 00 A/Solomon Islands/03/2006-like (H1N1) 00 A/Wisconsin/67/2005-like (H3N2) 26 Primary endpoint Subjects with culture-positive CDC-ILI, n (%) 1 (0.04)4 (0.2) Protective Efficacy, % (95% CI) 75.4 (-148.0, 99.5) 30

PSC04: Clinical Efficacy Virus Isolates FluBlok N=2344 Placebo N=2304 Summary of virus isolation results Subjects from whom a NS/TS was obtained, n (%) 273 (11.6)309 (13.4) Subjects with positive cultures, n (%) 64 (2.7)114 (4.9) Number of isolates B/Florida/04/2006-like (different lineage) 2335 B/not determined 01 A/Solomon Is/03/06-like (H1N1) (vaccine-related) 00 A/Brisbane/59/2007-like (H1N1) (drift variant) 39 A/Wisconsin/67/2005-like (H3N2) (vaccine-related) 26 A/Brisbane/10/2007-like (H3N2) (drift variant) 1427 A/not determined (H3N2) 1725 A/not determined (unknown subtype)

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 32

PSC04: Clinical Efficacy Pre-specified Exploratory Endpoints FluBlok N=2344 Placebo N=2304 Pre-specified Exploratory endpoints Subjects with culture-positive CDC-ILI, n (%) any strain 44 (1.9)78 (3.4) Protective Efficacy, % (95% CI) 44.6 (18.8, 62.6) Subjects with CDC-ILI, regardless of culture results, n (%) 127 (5.4)162 (7.0) Protective Efficacy, % (95% CI) 22.9 (2.2, 39.4) 33

PSC04: Clinical Efficacy Against any Influenza Strain – Exploratory Endpoints FluBlok 135µg N=2344 Placebo N=2304 Clinical Efficacy in the prevention of influenza type A or B Subjects with culture-positive Influenza, n (%)64 (2.7)114 (4.9) Protective Efficacy, % (95% CI)44.8 (24.4, 60.0) Clinical Efficacy in the prevention of influenza type A Subjects with culture-positive CDC-ILI, n (%)26 (1.1)56 (2.4) Protective Efficacy, % (95% CI)54.4 (26.1, 72.5) Culture-positive subjects, n (%)41 (1.7)79 (3.4) Protective Efficacy, % (95% CI)49.0 (24.7, 65.9) 34

PSC04: Clinical Efficacy Against any Influenza Strain – Exploratory Endpoints (2) FluBlok 135µg N=2344 Placebo N=2304 Clinical Efficacy in the prevention of influenza type A or B Subjects with culture-positive Influenza, n (%)64 (2.7)114 (4.9) Protective Efficacy, % (95% CI)44.8 (24.4, 60.0) Clinical Efficacy in the prevention of influenza type B Subjects with culture-positive CDC-ILI, n (%)18 (0.8)23 (1.0) Protective Efficacy, % (95% CI)23.1 (-49.0, 60.9) Culture-positive subjects, n (%)23 (1.0)36 (1.6) Protective Efficacy, % (95% CI)37.2 (-8.9, 64.5) 35

Vaccine Efficacy in other Studies 36 AuthorVaccine Efficacy 1 Comments Bridges et al., %Poor Match Belongia et al., % 21% 52% 2004/05: poor match 2005/06: poor match 2006/07: good match Beran et al., %2005/06: poor match (B-lineage mismatch) Skowronski et al., %2006/07: high efficacy against match strain Monto et al., % for TIV 36% for LAIV 2007/08: only 9% B- viruses vs. >35% in PSC04 1 Reduction in culture confirmed influenza

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

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 39

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 40

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 Years Results published: Treanor JJ et al. JAMA 297:

42 PSC01: Design  Phase 2/3 field study during 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

PSC01: Demographics  Age group  Mean Age - 31  M/F % - 37/63  Race/Ethnicity –White/Caucasian85% –Black/African-American6% –Latino/Hispanic3% –Asian3% –American Indian/Alaska Native1% –Native Hawaiian/Pacific Islander1% –Other2% 44

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).

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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

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PSC01: Clinical Efficacy Virus Isolation 53 Number (%) of Subjects Study Treatment FluBlok Overall N=301 FluBlok 75µg N=150 FluBlok 135µg N=151 Placebo N=153 Summary of virus isolation results Total no. subjects from whom NP swabs were obtained (flu symptom score ≥ 2) 39 (26)34 (23)43 (28)73 (24) Number of isolates4 (2.7)1 (0.7)8 (5.2)5 (1.7) H3N24064 H1N10000 B0121

PSC01: Clinical Efficacy Pre-specified Endpoints Number (%) of Subjects FluBlok 75µg N=150 FluBlok 135µg N=151 Placebo N=153 FluBlok Overall N=301 Pre-specified efficacy endpoints Subjects with culture-positive CDC-ILI (%) 2 (1)07 (5)2 (1) Protective Efficacy (%) (95% CI) (-53.1, 97.0)(29.7, 100)(23.7, 98.5) Subjects with CDC-ILI regardless of influenza culture results (%) 14 (9)9 (6)20 (13)23 (8) Protective Efficacy (%) (95% CI) (-48.6, 66.6)(-4.8, 81.7)(-12.2, 69.3) Placebo vs FluBlok 135 µg rHA (p-value) Placebo vs FluBlok Overall (p-value)

PSC01: Clinical Efficacy – Post Hoc Endpoints Number (%) of Subjects Study Treatment FluBlok Overall N=301 FluBlok 75µg N=150 FluBlok 135µg N=151 Placebo N=153 Subjects with culture-positive CDC-ILI due to A/H3N2 2 (1.3)0 (0)5 (3.3)2 (0.7) Protective Efficacy (%) (95% CI) (-149.2, 96.1)(-10.6, 100)(-24.2, 98.1) Subjects with culture- confirmed symptomatic illness, regardless of whether the subject met the case definition for CDC-ILI 4 (3)1 (1)8 (5)5 (2) Protective Efficacy (%) (95% CI) (-90.4, 88.8)(5.5, 99.7)(-10.1, 91.8) 55

56 Data restricted to 135µg formulation.

57 Data restricted to 135µg formulation. *Fever defined as ≥99.6°F (37.6°C) in this study

PSC01: Additional Safety Data Unsolicited AEs –Reported in 35% FluBlok vs. 42% placebo –Headache, URI most commonly reported –No imbalances between study groups SAEs (FluBlok) –Seizure secondary to hypoglycemia on Day 26 –Lobular carcinoma in situ on Day 55 –Both classified as “unrelated” No study withdrawals due to AEs

PSC06 59 Evaluation of the Safety and Reactogenicity of FluBlok, Trivalent Recombinant Baculovirus-Expressed Hemagglutinin Influenza Vaccine, and Comparison of the Immunogenicity, Efficacy and Effectiveness of FluBlok to a Licensed Egg-Grown Influenza Vaccine (Fluzone) in Adults Aged 50 to 64

PSC06: Design  602 healthy, medically stable adults age years assigned either a single dose of FluBlok or commercially available trivalent influenza vaccine (Fluzone) during  Objectives were to evaluate safety & reactogenicity and compare immunogencity & efficacy to an active control 60

PSC06: Vaccine and Distribution  300 subjects received FluBlok - a single dose with 45µg of three rHAs (135µg total rHA)  302 subjects received TIV (Fluzone) - a single dose containing 15µg of three HAs (45µg total HA) –A/Solomon Islands/3/06 (H1N1) –A/Wisconsin/67/05 (H3N2) –B/Malaysia/2506/04 (B/Victoria) 60

PSC06: Demographics  Age group  Mean age - 56  M/F% - 38/62  Race/Ethnicity –White/Caucasian73% –Black/African-American4% –Latino/Hispanic8% –Asian12% –Native Hawaiian/Pacific Islander<1% –Other4% 62

63 PSC06: 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%

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PSC06: Seroconversion 65 Day 28 No. of Subjects (%) FluBlok (N=299) Fluzone (N=302) A/Solomon Islands/03/06 (H1N1) No. (%) with seroconversion 216 (72)200 (66) 2-sided 95% CI (66.8,77.2)(60.6,71.5) A/Wisconsin/67/05 (H3N2) No. (%) with seroconversion 183 (61)132 (44) 2-sided 95% CI (55.4,66.8)(38.0,49.5) B/Malaysia/2506/04 No. (%) with seroconversion 122 (41)124 (41) 2-sided 95% CI (35.2,46.6)(35.5,46.8) Green: Meets FDA criterion for non-inferiority Red: Does not meet criterion for non-inferiority

66 PSC06: 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

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PSC06: Seroprotection 68 Day 28 No. of Subjects (%) FluBlok (N=299) Fluzone (N=302) A/Solomon Islands/03/06 (H1N1) No. (%) seroprotected288 (96)289 (96) 2-sided 95% CI(93.5, 98.1)(92.8, 97.7) A/Wisconsin/67/05 (H3N2) No. (%) seroprotected255 (85)227 (75) 2-sided 95% CI(80.8, 89.1)(69.9, 79.9) B/Malaysia/2506/04 No. (%) seroprotected278 (93)285 (94) 2-sided 95% CI(89.5, 95.6)(91.1, 96.7)

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PSC06: Non Inferiority Comparison FluBlok versus Fluzone  The upper bound of the two-sided 95% CI on the ratio of the GMTs (GMT US licensed vaccine/GMT new vaccine) should not exceed 1.5  The upper bound of the two-sided 95% CI on the difference between the seroconversion rates (Seroconversion US licensed vaccine - Seroconversion new vaccine) should not exceed 10% 70

PSC06: Non Inferiority Comparison FluBlok versus Fluzone StrainsGMT Ratio GMT TIV/ GMT FluBlok Difference in seroconver- sion rates A/Solomon Island/3/2006 (H1N1) 0.77 [0.75, 0.79] -6% [-13, 1] A/Wisconsin/67/2005 (H3N2) 0.58 [0.53, 0.62] -17.5% [-25, -10] B/Malaysia/2506/ [1.01, 1.09] 0.3% [-8, 8] 71

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73 *Fever defined as >100.4°F in this study

PSC06: Additional Safety Data  Unsolicited AEs –Reported in 14% of FluBlok and 17% of Fluzone recipients  FluBlok: erythema at injection site in the immediate post- vaccination period (2%) and cough (2%) most commonly reported  Fluzone: pharyngolaryngeal pain (3%) and rhinorrhea (2%) most commonly reported –Several imbalances noted between study groups (in both directions) No clinically concerning patterns upon further review –20 FluBlok recipients (7%) and 22 Fluzone recipients (7%) had AEs classified as “related” or “possibly related” to study vaccine  Most were signs and symptoms of URI –No subjects withdrew as consequence of AEs 74

PSC06: Additional Safety Data  Serious Adverse Events –Four SAEs reported in 4 subjects, including two in each treatment group –FluBlok  Vasovagal syncope 10 minutes post vaccination (related)  Acute pancreatitis (unrelated) –Fluzone  Prostate cancer (unrelated)  CVA (unrelated) –No deaths reported 75

PSC03 Comparison of the Immunogenicity, Safety and Reactogenicity of FluBlok, Trivalent Recombinant Baculovirus-Expressed Hemagglutinin Influenza Vaccine, to a Licensed Egg-Grown Influenza Vaccine (Fluzone) in Ambulatory Elderly Adults Keitel WA et al.: In Press. Vaccine

77 PSC03: Design  Phase 2/3 field trial during in medically stable adults aged 65 or older were randomized to receive either FluBlok containing 45 µg of the three rHAs (135µg total rHA) or TIV (Fluzone) containing 15 µg of the three HAs (45 µg total HA)  Objectives were to evaluate the safety, immunogenicity, and protective efficacy of FluBlok versus a licensed TIV

PSC03: Vaccine & Subject Distribution  436 subjects received FluBlok - single dose: 45µg of three rHAs (135µg total) recommended by WHO, CDC, and FDA’s VRBPAC –A/New Caledonia/20/99 (H1N1) –A/Wisconsin/67/95 (H3N2) –B/Ohio/01/05 (B/Victoria)  433 subjects received Fluzone - single dose: 15µg of the three HAs (45µg total HA) –Note: Fluzone included B/Malaysia/2506/2004 because TIV manufacturers switched strains 78

PSC03: Demographics  Age group ≥65  Mean age - 73  M/F % - 48/52  Race/Ethnicity –White/Caucasian99% –Black/African-American<1% –Latino/Hispanic<1% –Other<1% 79

80 PSC03: 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 30%

PSC03: Seroconversion or Significant Increase HI Titers Day 28 81

PSC03: Seroconversion 82 STRAINS SUBJECTSSUBJECTS ≥ 75 FluBlok N=431 Fluzone N=430 FluBlok N=163 Fluzone N=159 Number Of Subjects (%) [95% CI] A/New (H1N1) Seroconversion [2-sided 95% CI] 187 (43) [38.7, 48.1] 140 (33) [28.1, 37.0] 64 (39) [31.8, 46.8] 48 (30) [23.1, 37.3] A/Wisconsin (H3N2) Seroconversion [2-sided 95% CI] 335 (78) [73.5, 81.6] 248 (58) [52.8, 62.4] 129 (79) [72.9, 85.4] 86 (54) [46.3, 61.8] B/Ohio (FluBlok) or B/Malaysia (Fluzone) Seroconversion [2-sided 95% CI] 126 (29) [25.0, 33.8] 168 (39) [34.4, 43.9] 43 (26) [19.6, 33.1] 56 (35) [27.8, 42.6]

83 PSC03: 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 60% in adults ≥65 years of age

PSC03: Seroprotection 84 All Subjects ≥75 Years

PSC03: Seroprotection - EOIS 85

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87 PSC03: Non Inferiority Comparison FluBlok versus Fluzone  The upper bound of the two-sided 95% CI on the ratio of the GMTs (GMT US licensed vaccine/GMT new vaccine) should not exceed 1.5  The upper bound of the two-sided 95% CI on the difference between the seroconversion rates (Seroconversion US licensed vaccine - Seroconversion new vaccine) should not exceed 10%

PSC03: Non Inferiority Comparison FluBlok versus Fluzone StrainsGMT Ratio GMT TIV/GMT FluBlok Difference in seroconver- sion rates A/New Caledonia (H1N1) 0.84 [0.81, 0.86] -11% [-17, -4] A/Wisconsin (H3N2)0.59 [0.57, 0.60] -20% [-26, -14] B/Ohio or B/Malaysia 1.30 [1.26, 1.34] 10% [4, 16] 88

89

90 *Fever defined as >100.4°F in this study

PSC03: Additional Safety Data  Unsolicited AEs –Reported in 21% of FluBlok and 20% of Fluzone recipients –Injection site reactions, headache, URI symptoms most commonly reported –Primary imbalance between treatment groups was a higher rate of injection site reactions in FluBlok recipients vs. Fluzone:  Erythema: 2.5% vs. 0.23%  Swelling: 1.1% vs. 0.23%  Bruising: 1.38% vs. 0.7% –Most injection site reactions were detected in the immediate post-vaccination period by the investigator  None required treatment  None associated with limitations in routine activity  Almost all resolved within 7 days –No subjects withdrew as consequence of AEs 91

PSC03: Additional Safety Data  Serious Adverse Events –70 SAEs reported in 70 subjects (8.1%)  36 in FluBlok recipients (8.3%)  34 in Fluzone recipients (7.9%) –Two deaths in each study group, considered unrelated  FluBlok (2) - perforated viscus with secondary peritonitis; brain stem hemorrhage  Fluzone (2) - CAD; cardiac arrest [diabetic] –No demonstrable imbalances in SAEs between study groups –All SAEs in each group classified as “unrelated” 92

Immunogenicity Across Studies 93

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102 PSC01PSC04PSC06PSC03 Adults age yrs Adults age yrs Adults age yrs Adults age ≥65 yrs FluBlokPlaceboFluBlokPlaceboFluBlokFluzoneFluBlokFluzone Number of Subjects Local Adverse Events Pain 61%17%37%8%51%55%22%23% Redness 5%2%4%2%8% 10%12% Swelling 10%3% 2%8%10%11%13% Bruising 7%4%3% 5% 3%5% Solicited Adverse Events - Overview

103 PSC01PSC04PSC06PSC03 Adults age yrs Adults age yrs Adults age yrs Adults age ≥65 yrs FluBlokPlaceboFluBlokPlaceboFluBlokFluzoneFluBlokFluzone Number of Subjects Systemic Adverse Events Headache 42%41%15%16%20%21%11%9% Fatigue 16%18%15% 13%21%9%10% Muscle Pain 20%12%11%7%13%14%7%9% Fever 0%1%<1% 1%<1% 0% Joint pain 5% 4% 5%6%5%6% Nausea 8%6% 5%4%5%4%3% Chills 3%2%3% 4%5%4% Sweating 3%5%NA 3%2% Solicited Adverse Events - Overview

104 FluBlok Protein Sciences Corporation Presentation Introduction Manon Cox, PhD, MBA Chief Operating Officer Protein Sciences Corporation Efficacy Immunogenicity Safety John Treanor, MD Principal Investigator University of Rochester Summary Benefit/Risk Conclusion Manon Cox, PhD, MBA Chief Operating Officer Protein Sciences Corporation

105 Summary Immunogenicity: Serum HI Antibody PSC01PSC04PSC06PSC yrs yrs≥ 65 yrs FluBlok FluzoneFluBlokFluzone A/H1N1A/New Caledonia A/Solomon Islands A/New Caledonia % Seroprotected %Seroconversion A/H3N2A/WyomingA/Wisconsin % Seroprotected %Seroconversion BB/JiangsuB/Malaysia B/OhioB/Malaysia %Seroprotected %Seroconversion

H1H3B GMT06FB>Fz 03FB>Fz % SCR06FB>Fz 03FB>Fz Fz>FB NINot NI FB>Fz :FB signif. higher p<0.05 Fz>FB :Fz signif. higher p< 0.05 Non Inferiority Comparison: FluBlok Compared to Fluzone

Immunogenicity Summary – Across Studies  Seroconversion and Seroprotection: –PSC03 and PSC06, combined:  FluBlok met 10 of 12 [83%] endpoints*  Fluzone met 9 (or 8) of 12 [75%] endpoints* –PSC01, PSC04, PSC03 and PSC06, combined  FluBlok met 21 of 24 [88%] of endpoints*  Non-inferiority versus TIV: –PSC03 and PSC06, combined:  FluBlok was non-inferior* to Fluzone in 11 of 12 (92%) comparisons *Seroconversion, Seroprotection, and Non-inferiority criteria based on FDA’s 2007 Seasonal Influenza Guidance Document. 107

FluBlok: PSC04 Summary of Efficacy 108 FluBlok is efficacious despite suboptimal match (95% drift)

FluBlok: Summary of Efficacy (2) 109  PSC01 (Placebo-controlled): 100% (95% CI 29.7, 100) efficacious despite suboptimal match  PSC03 and PSC06 (Active-controlled): # of cases too small to draw meaningful conclusions

FluBlok: Summary of Safety Data  Commercial formulation evaluated in a total of 3,233 adults in 4 randomized, controlled trials –2497 adults age yrs –300 adults age yrs –436 adults age >65 yrs  Excellent tolerability and safety profile, with AE rates generally similar to the active comparator, Fluzone in two studies  Only one treatment-related SAE (vasovagal syncope) and one possibly-related SAE (pericardial/pleural effusion) reported 110

FluBlok: Post Marketing Surveillance Objectives:  Examine Multiple Doses of FluBlok  Monitor Safety in Large Observational Post Marketing Study 111

Conclusions  FluBlok addresses a medical need as it can be used in egg-allergic subjects  FluBlok manufacturing process does not use eggs  Short production time and ability to match strains offers advantages  The higher antigen content potential provides additional benefits to those at greater risk for influenza FluBlok is expected to provide a significant public health benefit 112