Vaccines and Related Biological Products Advisory Committee Meeting

1. Vaccines and Related Biological Products Advisory Committee Meeting CBER Clinical Review of Immunogenicity Data Supporting the Effectiveness of Prevnar 13 for the Prevention of Pneumococcal Disease in Adults Aged ≥ 50 Years Applicant: Wyeth Pharmaceuticals Inc. Tina Khoie, M.D., M.P.H FDA/CBER/OVRR/DVRPA November 16, 2011

2. Presentation Outline • Prevnar 13 clinical development program in adults • Primary non-inferiority studies evaluating a single dose of Prevnar 13 (PCV13) compared to a single dose of Pneumovax 23 (23vPS) • Supportive concomitant immunization studies with inactivated trivalent influenza vaccine (TIV) and PCV13 • Supportive data on the sequential use of Prevnar 13 with Pneumovax 23

3. Prevnar 13 Clinical Development Program in Adults • Included five multicenter phase 3 studies conducted in the United States and/or Europe • Studies enrolled immunocompetent adults with pre-existing stable* medical conditions. • Anti-pneumococcal antibody response evaluation • Functional opsonophagocytic antibodies (OPA) measured by a microcolony OPA assay 1 month post-vaccination to each of the 13 pneumococcal serotypes contained in Prevnar 13 *Stable medical condition was defined as disease not requiring significant change in therapy or hospitalization for worsening disease 12 weeks before receipt of study vaccine.

4. Five Phase 3 Immunogenicity Studies in Adults N = number vaccinated with at least 1 study dose of PCV13 or 23vPS. *Sequential use of PCV13 and 23vPS was an exploratory or secondary objective.

5. Pneumococcal Serotypes Evaluated • 12 common serotypes contained in both PCV13 and 23vPS • Serotype 6A - unique to PCV13 • 11 unmeasured serotypes unique to 23vPS

6. Primary Immunogenicity StudiesStudy 004: 23vPS-naïve 50-64 yr oldsStudy 3005: Pre-immunized ≥ 70 yr olds

7. Study 6115A1-004 • Previously unvaccinated 50 to 64 year old adults were enrolled into one of two study cohorts based on age: • 60-64 Year Olds (N=831) • Randomized, active-controlled, and modified double-blinded • Subjects randomized (1:1) to receive a single dose of PCV13 or 23vPS • Co-primary objectives: • For each of the 12 common serotypes, to demonstrate non-inferiority (NI) of serotype-specific immune responses induced by PCV13 compared to 23vPS • For serotype 6A, to demonstrate a statistically significantly greater (SSG) anti-6A response after PCV13 compared to 23vPS • 50-59 Year Olds (N=404) • Open-label: all subjects received 1 dose of PCV13 • Primary objective: For the PCV13 serotypes, to demonstrate non-inferiority of the serotype-specific immune responses elicited by PCV13 in 50-59 yr olds compared to 60-64 yr olds

8. Study 004: Primary Analyses & Success Criteria

9. Study 004: Primary Objective Results

10. Study 004: OPA GMTs in 23vPS-Naïve 60-64 Yr Olds Primary endpoint: NI criterion (LL > 0.5) met for each of the 12 common serotypes.

11. Study 004: OPA GMTs in 23vPS-Naïve 60-64 Yr Olds Secondary endpoint: LL > 1.0 for 8 of the 12 common serotypes.

12. Study 004: Anti-6A OPA Titers in Naïve 60-64 Yr Olds aSSG: statistically significantly greater b Primary endpoint c Secondary endpoint A statistically significantly greater proportion of PCV13 recipients achieved a ≥ 4-fold increase in OPA titers to serotype 6A compared to 23vPS recipients.

13. Study 004: OPA GMTs in 23vPS-Naïve 50-59 and 60-64 Yr Olds Primary endpoint: NI criterion (LL > 0.5) met for each Prevnar 13 serotype.

14. Study 6115A1-3005 • ≥ 70 year olds with 1 prior 23vPS dose ≥ 5 years prior to enrollment • Randomized (1:1), active-controlled, modified double-blind • Primary objectives and success criteria identical to study 004 • Secondary and exploratory objectives: assessed immune response to the study dose administered at year 1

15. Study 3005:Primary Year 0 Objective Results

16. Study 3005: OPA GMTs in Pre-immunized ≥ 70 Yr Olds Primary endpoint: NI criterion (LL > 0.5) met for each of the 12 common serotypes.

17. Study 3005: OPA GMTs in Pre-immunized ≥ 70 Yr Olds Secondary endpoint: LL > 1.0 for 10 of the 12 common serotypes.

18. Study 3005: Anti-6A OPA Titers in Pre-immunized ≥ 70 Yr Olds aSSG: statistically significantly greater b Primary endpoint c Secondary endpoint A statistically significantly greater proportion of PCV13 recipients achieved a ≥ 4-fold increase in OPA titers to serotype 6A compared to 23vPS recipients.

19. Phase 3 Studies Evaluating Concomitant PCV13 and TIV* in 23vPS-Naïve Adults Study 3001: 50-59 Year Olds Study 3008: ≥ 65 Year Olds *The TIV vaccine used in studies 3001 and 3008 was U.S. licensed Fluarix (GSK) for the 2007-2008 influenza season.

20. Study 3001 • 50-59 year olds naïve to 23vPS • Randomized (1:1) and double-blinded • Co-primary objectives: To demonstrate that immune responses induced by PCV13 and TIV, when administered concomitantly, are non-inferior to the corresponding immune responses induced by: • TIV alone, as measured by standard HAI titer elicited by each of the three TIV antigens one month after vaccination with TIV in all subjects; and • PCV13 alone, as measured by serotype-specific pneumococcal IgG GMCs one month after vaccination with PCV13 in a subset of 562 subjects. • Descriptive (post-hoc): OPA assays performed on subset of 607 subjects

21. Study 3001: % Achieving ≥ 4-Fold Increase in HAI Titer for TIV Antigens (23vPS-Naïve 50-59 Yr Olds) NI criterion (LL of 95% CI for the difference in proportions > -10%) met for each TIV antigen.

22. Study 3001: Anti-Pneumococcal OPA GMTs, Naïve 50-59 Yr Olds Exploratory analysis: a LL > 0.5 was observed for eight PCV13 serotypes.

23. Study 3008 • 23vPS-Naïve Adults Aged ≥ 65 Years Naïve • Randomized (1:1), double-blinded • Primary objectives identical to study 3001 • Primary endpoints: HAI titers for TIV antigens measured for all subjects; pneumococcal IgG GMCs measured in a subset of 605 subjects. • Descriptive (post-hoc): OPA assays performed on a subset of 541 subjects.

24. Study 3008: % Achieving ≥ 4-Fold Increase in HAI Titer to TIV Antigens (23vPS-Naïve ≥ 65 Yr Olds) Non-inferiority criterion (LL of 95% CI for the difference in proportions > -10%) met for two of the TIV antigens; non-inferiority was not met for A/H3N2.

25. Study 3008: Anti-Pneumococcal OPA GMTs, Naïve ≥ 65 Yr Olds Exploratory analysis: a LL > 0.5 was observed for ten PCV13 serotypes.

26. Phase 3 Studies Assessing Two-Dose Vaccine Sequences with PCV13 and 23vPS Study 3005: Pre-immunized ≥ 70 Year Olds (1 year dosing interval) Study 004: 23vPS-Naïve 50 to 64 Yr Olds (3-4 year dosing interval) Study 3010: 23vPS-Naïve 60 to 64 Year Olds (1 year dosing interval)

27. Extension of Study 004 • Study protocol revised about 2 years after completion of cohort 2 to add a second open label study vaccination about 3-4 years after the initial study vaccination. • Vaccination 2 analyses were descriptive; no formal power calculations performed.

28. Study 3010 • Adults aged 60-64 yrs naïve to 23vPS (N=650) • Randomized (3:5:4), active-controlled, modified double-blind • 2 doses administered 1 year apart

29. PCV13/23vPS vs 23vPS Subjects in studies 004 and 3010 were 23vPS-naïve. LL: lower limit. Primary and secondary comparisons in black font. Exploratory comparisons in italicized font. A dose of 23vPS administered 1 or 3-4 years after PCV13 did not result in diminished OPA GMTs when compared to the OPA GMTs elicited by a single dose of 23vPS. Results suggest that a more expanded dosing interval of 3-4 years in group 1 resulted in higher OPA GMTs for more serotypes following the 2-dose sequence, when compared to a 1 year dosing interval.

30. PCV13/23vPS vs PCV13 Subjects in studies 004 and 3010 were 23vPS-naïve. LL: lower limit. UL: upper limit. Secondary comparison in black font. Exploratory comparisons in italicized font. A two dose regimen with a 3-4 year interval resulted in OPA GMTs for 11 of the 13 serotypes that are at least half of the OPA GMTs achieved after an initial dose of PCV13. A dose of 23vPS administered 1 year after PCV13 elicited OPA GMTs that were lower for 8 serotypes than the OPA GMTs elicited by a single dose of PCV13.

31. PCV13/PCV13 vs PCV13/23vPS Subjects in studies 004 and 3010 were 23vPS-naïve. LL: lower limit. UL: upper limit. Exploratory comparisons in italicized font. OPA GMTs following 2 doses of PCV13 were at least half of the corresponding OPA GMTs following a sequence of PCV13/23vPS for several, but not all, of the PCV13 serotypes. Responses were also noted to be lower for 5 serotypes among subjects who received two doses of Prevnar 13 compared to a sequence of PCV13/23vPS. These observations apply to both the 1 and 3-4 year dosing interval.

32. PCV13/PCV13 vs PCV13 Subjects in studies 004 and 3010 were 23vPS-naïve. Subjects in study 3005 were pre-immunized. LL: lower limit. UL: upper limit. Secondary comparisons in black font. Exploratorycomparisons in italicized font. OPA GMTs following two PCV13 doses given 3-4 years apart in 50-64 year olds or 1 year apart in ≥ 70 year olds were at least half of the OPA GMTs following a single dose of PCV13 for 12-13 serotypes. In 60-64 year olds, OPA GMTs achieved following two doses of PCV13 given 1 year apart resulted in lower OPA GMTs for 7 serotypes compared to the OPA GMTs elicited by a single dose of PCV13.

33. Sequential Dose Comparisons (Continued) Study 3010 subjects were 23vPS-naïve. Primary and secondary comparisons in black font. Exploratory comparisons in italicized font. When comparing PCV13/23vPS to 23vPS/PCV13 in 60-64 year olds with a one year dosing interval, higher OPA GMTs were achieved for 11 of the 12 common serotypes. In exploratory comparisons between 23vPS/PCV13 (given 1 year apart) and a single dose of 23vPS in 60-64 year olds, results suggest lower OPA GMTs were achieved for 10 serotypes following the 2-dose sequence.

34. Summary and Conclusions The PCV13 adult clinical program demonstrated that: • In pneumococcal vaccine naïve 60-64 year olds and 23vPS pre-immunized ≥ 70 year olds: • Functional antibody responses induced by a single dose of PCV13 to each of the 12 common serotypes were non-inferior to the corresponding responses induced by a single dose of 23vPS. • A single dose of PCV13 elicited a statistically significantly greater OPA titer to serotype 6A compared to a single dose of 23vPS. • In 50-59 year old adults, functional antibody responses induced by a single dose of PCV13 to each of the 13 vaccine serotypes were non-inferior to the corresponding responses induced by a single dose of PCV13 in 60-64 year old adults. • In pneumococcal vaccine naïve adults ≥ 50 years of age, exploratory data suggest that concomitant administration of PCV13 and TIV generally results in lower anti-pneumococcal OPA GMTs compared to administration of PCV13 alone.

35. Summary and Conclusions (continued) • Information gaps regarding the sequential use of PCV13 and 23vPS: • Antibody responses to the 11 pneumococcal serotypes unique to 23vPS were not evaluated. • Most data were exploratory and/or in-completely addressed the following: • the optimal timing of 23vPS when given in sequence with PCV13; • the duration of immunity; and • the clinical benefit of re-vaccination, if any. • In the absence of an established correlate of protection for pneumococcal disease (invasive and non-invasive), clinical benefit will need to be confirmed in the phase 4 CAPITA trial.

36. Thank You