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Vaccines and Related Biological Products Advisory Committee Meeting

Vaccines and Related Biological Products Advisory Committee Meeting. Influenza Vaccine, Recombinant Hemagglutinin FluBlok Protein Sciences Corporation Cynthia Nolletti, MD FDA/CBER/OVRR/DVRPA November 19, 2009. Presentation Outline. Product Summary Regulatory History Clinical Overview

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Vaccines and Related Biological Products Advisory Committee Meeting

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  1. Vaccines and Related Biological Products Advisory Committee Meeting Influenza Vaccine, Recombinant HemagglutininFluBlokProtein Sciences Corporation Cynthia Nolletti, MD FDA/CBER/OVRR/DVRPA November 19, 2009

  2. Presentation Outline • Product Summary • Regulatory History • Clinical Overview • Clinical Trials • PSC04 • PSC06 • PSC03 • PSC01 • Summary of Efficacy and Immunogenicity • Overview of Safety • Overall Conclusions • Questions for the Committee

  3. Product Summary • Product: trivalent recombinant hemagglutinin influenza vaccine consisting of three recombinant influenza hemagglutinin antigens derived from H1, H3, and B strains, inserted into a baculovirus vector, and expressed in Spodoptera frugiperda insect cells. • Proper name: Influenza Vaccine, Recombinant Hemagglutinin • Proprietary name: FluBlok • Proposed Indication: For active immunization of adults 18 years of age and older against influenza disease caused by influenza virus subtypes A and type B represented in the vaccine. • Dosage Form and Route of Administration: 135μg influenza HA antigen (45μg per influenza virus strain) per 0.5mL dose administered as a single dose intramuscularly.

  4. Regulatory History • October 23, 2004 – original IND filed • December 11, 2006 - Fast track granted • September 21, 2007 – Pre-BLA meeting • April 18, 2008 – Original BLA submission requesting accelerated approval. • August 29, 2008 – Complete Response letter issued. • April 28, 2009 – Complete Response submitted with additional clinical efficacy data. Traditional approval requested.

  5. Clinical Overview • Data from four clinical trials (one phase 2, three phase 3) submitted in support of approval of the 135μg dose • Two placebo-controlled and two active-controlled trials • Safety population: 3233 FluBlok recipients • 23% ≥ 50 years of age; 13% ≥ 65 years of age • Vaccine efficacy population: 2344 FluBlok recipients • 100% 18 to 49 years of age • Immunogenicity population: 1323 FluBlok recipients • 55% ≥ 50 years of age; 32% ≥ 65 years of age

  6. Clinical Trials Overview *n=evaluable population for safety and clinical efficacy analyses **135μg dose group MDB = modified double-blind, person administering vaccine not blinded.

  7. Clinical Overview: Immunogenicity Assessments Immunogenicity endpoints were assessed using the hemagglutinin inhibition (HAI) assay and FDA criteria for acceptable immune responses.* Although there is no established immune correlate of protection, the HI response may be an acceptable surrogate marker of activity that is reasonably likely to predict clinical benefit. Previous studies suggest that HI titers of ≥ 1:40 correlate with protection against illness. * Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines (May 2007). 7

  8. Clinical Overview: Immunogenicity Assessments The HAI assay and influenza viral cultures (nasal swab/throat swabs) were performed at a single central laboratory. A validated assay using BEVS-derived* antigens was used to test sera from all treatment groups in the phase 3 studies. Egg-derived HA antigens were used in the phase 2 study. *BEVS=baculovirus expression vector system 8

  9. Clinical Overview: Immune Response Endpoints • Seroconversion rate (SCR): defined as the proportion of subjects with: • Pre-vaccination HI titer < 1:10 and a post-vaccination titer ≥ 1:40, or • Pre-vaccination HI titer ≥ 1:10 and a minimum 4-fold rise in post-vaccination titer. • Proportion of subjects achieving a post-vaccination HI titer ≥ 1:40 • HI titers were drawn on Days 0 and 28 in all studies

  10. Clinical Overview FDA Immune Response Acceptance Criteria • For adults < 65 years of age: • The lower bound of the two-sided 95% CI (LB) for the SCR should meet or exceed 40%. • The LB for the proportion of subjects achieving a post-vaccination HI antibody titer ≥ 1:40 should meet or exceed 70%. • For adults ≥ 65 years of age: • LB for SCR should be ≥ 30% • LB for post-vaccination HI ≥ 1:40 should be ≥ 60%.

  11. Clinical OverviewNon-inferiority Endpoints and Acceptance Criteria • GMT ratio of TIV to FluBlok 28 days post-vaccination for each vaccine strain • The upper bound of the 2-sided 95% CI (UB) on the GMT ratio should not exceed 1.5 • The difference between the SCRs of TIV and FluBlok: (SCR TIV – SCR FluBlok) • The UB should not exceed 10%.

  12. Clinical OverviewClinical Endpoint Assessments • For the clinical efficacy endpoint, absolute vaccine efficacy (VE) relative to placebo was assessed in young healthy adults in studies PSC04 and PSC01. • Vaccine Efficacy (VE) = (1 – RR) x 100 = (1- Pv/Pp) x 100 • RR = relative risk • Pv=proportion of FluBlok recipients and Pp=proportion of Placebo recipients who developed culture-confirmed ILI • For the active control studies PSC06 and PSC03, the Relative Efficacy (RE) (or % Relative Reduction) of FluBlok to Fluzone was calculated using descriptive statistics as: • RE = (1 – RR) x 100.

  13. Overview: Clinical Endpoint Assessments - ILI • Influenza-like Illness (ILI) was assessed using a Flu Symptom scoring card. Subjects were to contact the clinic if they scored 2 or more points: • 1 point: fever ≥ 100ºF oral • 1 point: cough, sore throat, or runny nose/stuffy nose • 1 point: muscle or joint aches, headache, chills/sweats, tiredness/malaise • CDC-ILI was defined as fever of ≥100°F oral accompanied by cough and/or sore throat on the same day or on consecutive days. • ILI was monitored by active and passive surveillance for 6 months and/or until the end of the influenza season (EOIS) (whichever was longer) in all studies.

  14. Study PSC04 Subjects 18 to 49 years of age

  15. Study PSC04 (2007-2008) • Phase 3 placebo-controlled trial of safety and efficacy in healthy young adults 18 to 49 years of age • Primary Objectives • Safety: to determine safety relative to placebo • Efficacy: to determine efficacy relative to placebo • Secondary Objectives • Immunogenicity: to assess immune responses to FluBlok according to acceptance criteria

  16. PSC04 (18-49yr): Design • Phase 3, prospective, randomized, double-blind, placebo-controlled • 4648 healthy adults age 18-49 years at 24 US sites • Randomized 1:1 FluBlok or placebo • Immunogenicity subset of 480 FluBlok recipients at 5 sites selected for immunogenicity analyses • Reactogenicity events collected through Day 7, Unsolicited AEs through Day 28, and SAEs through Day 180.

  17. PSC04 (18-49 yr): Efficacy Endpoints • Primary Efficacy Endpoint: • The proportion of subjects in each treatment group with culture-confirmed CDC-ILI associated with isolation of an influenza virus antigenically resembling vaccine strains (“matched” strains) • Vaccine Efficacy (VE) = (1 – RR) x 100 • PSC04 was powered to assess the LB of the two-sided 95% CI (LB) of VE around a point estimate of 70%. • Acceptance criteria: the LB of the 95% CI for VE of FluBlok relative to placebo should be ≥ 40%

  18. PSC04 (18-49 yr): Efficacy Endpoints • Secondary and Exploratory Efficacy Endpoints: • Proportion with culture-confirmed ILI (not necessarily CDC-ILI) due to matched strains. • Proportion with culture-confirmed ILI due to any (matched and mismatched) influenza virus strains.

  19. PSC04 (18-49 yr): Immunogenicity Endpoints • Immunogenicity Endpoints: • Seroconversion rate for each vaccine strain • Proportion of subjects with a Day 28 post-vaccination HI titer ≥ 1:40 for each vaccine strain

  20. PSC04 (18-49 yr): Disposition of Subjects *Does not include pregnancies **Serology available for immunogenicity analysis. Placebo serologies run as post hoc analysis.

  21. PSC04 (18-49 yr): Efficacy Results • 646 swabs from 583 subjects obtained during the 180-day surveillance period. • 64 (2.7%) FluBlok and 114 (4.9%) placebo had culture-confirmed ILI. • 2007-2008 vaccine strains were poorly matched to circulating viral strains. • 170 of 178 total isolates antigenically mismatched • 111 of 119 type A isolates antigenically mismatched • 58 of the 59 B isolates mismatched; 1 not typed

  22. PSC04 (18-49 yr): Vaccine Efficacy 22 *Includes one untyped B strain

  23. PSC04 (18-49 yr): Summary of Vaccine Efficacy • VE results for FluBlok against culture-confirmed ILI due to antigenically matched strains limited by small numbers of cases. • Point estimate of VE against culture-confirmed ILI for all strains regardless of antigenic match was 44.8%. • LB 95% CI of VE for type A strains was 24.7%, and for type B strains included zero.

  24. PSC04 (18-49): Immunogenicity Endpoints All 3 strains met both immunogenicity endpoints Acceptance criteria: *LB 95% CI ≥ 40%; **LB 95% CI ≥ 70%

  25. Study PSC06 Subjects 50 to <65 Years of Age

  26. Study PSC06 (50-64 yr) • Non-inferiority comparison of FluBlok to Fluzone in healthy adults 50 to 64 years of age. • Safety Objective: • to compare the safety and reactogenicity of FluBlok and Fluzone • Efficacy Objective: • to compare the relative efficacy of FluBlok and Fluzone in the prevention of culture-confirmed ILI • Immunogenicity Objective: • to compare the immunogenicity of FluBlok and Fluzone according to pre-specified non-inferiority criteria

  27. PSC06 (50-64 yr): Design • Phase 3, prospective, randomized, double-blind, active-controlled • 602 subjects at 5 sites in California and Hawaii • Randomized 1:1 FluBlok or Fluzone • Reactogenicity events collected through Day 7, Unsolicited AEs through Day 28, SAEs through Day 180

  28. PSC06 (50-64 yr): Efficacy Endpoints • Proportion with culture-confirmed ILI due to matched strains • Proportion with culture-confirmed ILI regardless of antigenic match • Statistical analyses for the clinical endpoints were descriptive

  29. PSC06 (50-64yr)Non-inferiority Endpoints • GMT ratio of Fluzone to FluBlok 28 days post-vaccination for each vaccine strain • The UB on the GMT ratio should not exceed 1.5 • The difference between the SCRs of Fluzone and FluBlok: (SCR Fluzone – SCR FluBlok) • The UB should not exceed 10%

  30. PSC06 (50-64 yr): Efficacy Results • There were no antigenically matched isolates. • The total numbers of antigenically mismatched isolates was small in both groups: FluBlok =7 and Fluzone = 4. • Case numbers are too small and the confidence intervals are too wide to draw meaningful conclusions regarding the relative risk of influenza illness in recipients of FluBlok compared to Fluzone in healthy adults 50 to 64 years of age. • Because the clinical endpoint data in this age group was not adequate, the immunogenicity data provided an important surrogate marker of clinical benefit (next slide)…

  31. PSC06 (50-64 yr)GMTs and GMT Ratio of Fluzone to FluBlok at Day 28 **UB 95%CI ≤ 1.5 *based on Statistical Reviewer’s adjustments for pre-vaccination titer, prior vaccination history, and assay variables.

  32. PSC06 (50-64yr)Difference in Seroconversion Rates at Day 28 *Acceptance criteria: UB 95%CI ≤ 10%.

  33. PSC06 (50-64 yr): Immunogenicity Results • FluBlok met all 6 endpoints establishing non-inferiority to Fluzone.

  34. Study PSC03 Subjects 65 years and older

  35. Study PSC03 (2006-2007) • Non-inferiority comparison of FluBlok to Fluzone in adults 65 years and older • Safety Objective: • To compare the safety and reactogenicity of FluBlok and Fluzone • Efficacy Objective: • To compare the relative efficacy of FluBlok and Fluzone in the prevention of culture-confirmed ILI • Immunogenicity Objective: • To compare the immunogenicity of FluBlok and Fluzone

  36. PSC03 (≥ 65 yr): Design • Phase 3, prospective, randomized, double blind, active-controlled • 870 medically stable adults ≥ 65 years of age at 6 US study sites • Randomized 1:1 FluBlok or Fluzone • Reactogenicity events through Day 7, Unsolicited AEs through Day 28, and SAEs through Day 180

  37. PSC03 (≥ 65 yr): Endpoints • Efficacy • Proportion of subjects in each vaccine group who experienced culture-confirmed CDC-ILI • Proportion who experienced any culture-confirmed medically attended acute respiratory illness • Descriptive statistics were used to calculate a Relative Efficacy of FluBlok to Fluzone: • RE = (1 – RR) x 100.

  38. PSC03 (≥ 65 yr): Non-inferiority Endpoints • GMT ratio of Fluzone to FluBlok • The difference in SCRs (Fluzone – FluBlok)

  39. PSC03 (≥ 65 yr): Clinical Efficacy Results • Of 53 sets of cultures, only 3 were positive, 2 Fluzone and 1 FluBlok, all three for influenza Type A. • The case numbers are too small and the confidence intervals are too wide to draw meaningful conclusions from study PSC03 regarding the relative risk of influenza illness in recipients of FluBlok compared to Fluzone in adults 65 years of age and older.

  40. PSC03 (≥ 65 yr): GMTs and GMT Ratios at Day 28 **UB 95% CI on GMT ratio ≤ 1.5 *Based on Statistical Reviewer’s adjustments for pre-vaccination titers and HI assay variables

  41. PSC03 (≥ 65 yr)Difference in Seroconversion Rates at Day 28 *UB 95% CI for (SCR TIV –SCR FluBlok) should be ≤ 10%

  42. PSC03 (≥ 65 yr)Immunogenicity Endpoint Results • FluBlok met 5 of the 6 primary endpoint criteria for demonstrating non-inferiority to Fluzone. • H1 and H3 antigens met both non-inferiority endpoints. • B strain demonstrated non-inferiority to Fluzone by the GMT ratio, but not by SCR criteria.

  43. Study PSC01 Subjects 18 to 49 Years of Age

  44. Study PSC01 (2004-2005) • Phase 2 dose-finding safety, immunogenicity and efficacy study in healthy adults 18 to 49 years of age • Safety Objective: • To determine safety relative to placebo • Immunogenicity Objective: • To compare the immunogenicity of two dose levels of FluBlok, 75µg versus 135µg total HA antigen* • Efficacy Objective: • To determine clinical efficacy in the prevention culture-confirmed ILI. *FluBlok 75µg = 15µg H1, 45µg H3, 15µg B strain FluBlok 135μg = 45μg per strain

  45. PSC01 (18-49 yr): Efficacy Endpoint • Clinical Efficacy • Proportion with culture-confirmed ILI • The study was not powered to test formal null hypotheses. Descriptive statistics were used to detect trends between the treatment groups.

  46. PSC01 (18-49 yr): Vaccine Efficacy Results *Blue shade: For these parameters both FluBlok dose group results (n=151 + 150) are included because both doses contained 45μg of the predominant H3N2 strain.

  47. PSC01 (18-49 yr): Vaccine Efficacy • Antigenically dissimilar H3N2 virus predominated • VE of the 135μg dose was 87.3% (LB 5.5%) against all culture-positive ILI and against all strains regardless of match. • Because H3N2 predominated and because both the 75 and 135µg dose groups contained 45µg of H3 antigen, if all cases from subjects who received the 75μg dose are included in the analysis, VE decreased to 68.2% (LB -10.1%). • The estimates of VE in study PSC01 suggest a favorable trend. However, this study was not powered to test a formal null hypothesis of vaccine efficacy and it is limited by the overall small sample size and wide confidence intervals.

  48. Clinical Efficacy and Immunogenicity Populations across Studies – FluBlok 135μg

  49. Summary: Vaccine Efficacy across Studies • PCS04 (18-49 yr) • Despite antigenic mismatch, overall VE against culture-confirmed illness due to any strain was 44.8% (LB 24.4%). • Point estimates against all type A and all type B influenza were 49.0% and 37.2% respectively. • Failed to meet primary endpoint against antigenically matched strains because mismatched circulating virus predominated. • PCS01 (18-49 yr) • Antigenic mismatch predominated. Descriptive statistics demonstrated a favorable trend towards VE: 87.3% (LB 5.5%) against all culture-confirmed ILI. • PCS03 and PSC06 (≥ 50 yr) • Unable to assess RE because of very small numbers of cases.

  50. Efficacy Conclusions In healthy adults (18 to 49 years), the VE of FluBlok against culture-confirmed influenza due to antigenically mismatched strains was 44.8% (LB 24.4%). The efficacy data is driven by study PSC04 (adults 18 to 49 years of age) where the sample size and the attack rate were adequate to assess absolute vaccine efficacy (VE) against placebo. 50

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