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Vaccines and Related Biological Products Advisory Committee Meeting Hepatitis B Vaccine (Recombinant), Adjuvanted (HEPLISAV): Review of Immunogenicity Alexandra S. Worobec, M.D., M.S. FDA/CBER/OVRR/DVRPA November 15, 2012. Outline. Proposed Indication SPR as an ‘effectiveness’ endpoint

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  1. Vaccines and Related Biological Products Advisory Committee MeetingHepatitis B Vaccine (Recombinant), Adjuvanted (HEPLISAV): Review of ImmunogenicityAlexandra S. Worobec, M.D., M.S.FDA/CBER/OVRR/DVRPANovember 15, 2012

  2. Outline • Proposed Indication • SPR as an ‘effectiveness’ endpoint • Dose Selection of 1018 ISS Adjuvant • Phase 3 studies of HEPLISAV: DV2-HBV-10 and DV2-HBV-16 • Trial design • Results: Immunogenicity

  3. HEPLISAV • Proposed Indication: active immunization against all subtypes of hepatitis B virus infection. • Adults 18-70 years of age • Dosage and Administration: • 0.5 mL dose • 20 mcg rHBsAg • 3000 mcg 1018 ISS adjuvant • Schedule is two doses given intramuscularly (IM), 1 month apart

  4. Seroprotection Rate: For the Evaluation of Hepatitis B Vaccine Effectiveness • Seroprotection Rate (SPR): • Anti-HBsAg level of 10 mIU/mL or greater recognized as conferring protection against hepatitis B virus infection • Higher absolute levels of anti-HBsAg antibodies are not indicative of a higher degree, or longer duration of protection, among responders

  5. Dose Selection of the 1018 ISS Adjuvant • Doses assessed (pilot Study DV2-HBV0001): 300, 650, 1000, or 3000 mcg of 1018 ISS adjuvant • Formulated with 20 mcg of rHBsAg • Population: HBsAg seronegative healthy adults, 18-55 years of age (n=48 total) • Results: Two IM doses of rHBsAg, 20 mcg, combined with 3000 mcg of 1018 ISS adjuvant, yielded the highest SPR rate with an acceptable safety profile.

  6. Phase 3 studies of HEPLISAV: DV2-HBV-10 and DV2-HBV-16

  7. Phase 3 Trial Study Design: Similar Study Designs for DV2-HBV-10 and DV2-HBV-16 • Subject and observer-blind, randomized, controlled study design • Engerix-B (GlaxoSmithKline Biologicals) used as the active comparator • Adult subjects seronegative for HBsAg, anti-HBsAg antibody (anti-HBsAg < 5 mIU/mL), and anti-HBcAg antibody, and who had never received any prior HBV vaccine, were enrolled • Excluded if high risk for recent exposure to HBV, HCV, or HIV

  8. Common Study Design Elements: Studies DV2-HBV-10 and -16 • Three injections • HEPLISAV: administered at Weeks 0 and 4; saline placebo at Week 24 • Engerix-B: administered at Weeks 0, 4, and 24

  9. Study DV2-HBV-10 • 21 sites in Canada and Germany • 11-55 years of age (ages 18-55 in Germany) • Randomized 3:1 to HEPLISAV:Engerix-B • 2415 subjects ≥ 18 years of age enrolled • n=1809 HEPLISAV • n=606 Engerix-B

  10. Primary Immunogenicity Endpoint and Criteria for Success • Primary immunogenicity endpoint: SPR after final active injection • Primary immunogenicity analysis: • difference in SPR between the Engerix-B group at Week 28 (4 weeks after the last active dose) and HEPLISAV group at Week 12 (8 weeks after the last active dose), • 2-sided 95% CI on the difference (Engerix-B minus HEPLISAV) in SPR evaluated • Success criteria: HEPLISAV SPR is non-inferior to Engerix-B if the upper limit of the 2-sided 95% CI on the difference in SPRs (Engerix-B minus HEPLISAV) < 0.10

  11. Additional Immunogenicity Endpoints in DV2-HBV-10 • SPR and geometric mean antibody concentrations (GMCs) for HEPLISAV vs. Engerix-B at all other study time points (Weeks 4, 8, 12, 24, and 28)

  12. Immunogenicity Analysis Populations • Per-Protocol Population: • Met eligibility criteria • No major protocol violations • Received all protocol-specified study injections • Anti-HBsAg measurements and all injections obtained within pre-specified windows • Modified Intent-to-Treat Population (mITT): • Received at least 1 study injection • Had 1 post-baseline anti-HBsAg level

  13. Subject Demographics Summary • Similar demographic and baseline characteristics: • Most white (~ 93%) or non-Hispanic/Latino (~ 97%) • Mean age ~ 40 years • Percentage of females (54%) slightly higher than males (46%) • > 99% of subjects had anti-HBsAg levels < 5 mIU/mL (definition of seronegative) • Majority non-smokers (63-64% for both treatment groups), non-diabetic (97%), and non-obese (BMI ≤ 30 kg/m2, 72-75% for both treatment groups)

  14. Subject Disposition Summary • 2428 subjects enrolled • 1809 adult subjects (≥ 18 years) assigned to HEPLISAV • 606 adult subjects assigned to Engerix-B • 97% of all adult subjects completed the study • Most common reason for subject discontinuation was “lost to follow-up” (1.7% of subjects in each group) • Enrollment included 13 adolescents (< 18 years) • 11 assigned to HEPLISAV • 2 assigned to Engerix-B • Not included in analysis

  15. Primary Immunogenicity Endpoint Analysis (Study DV2-HBV-10)SPR for HEPLISAV (Week 12) compared with Engerix-B (Week 28): Per-Protocol Analysis Population, Adults 18-55 Years of Age CI = Confidence interval, N = number of subjects with non-missing results in the analysis population in the treatment group, n = number of subjects with post-injection anti-HBsAg levels ≥ 10 mIU/mL a Estimated response (proportion), their difference, and associated confidence intervals are based on a statistical analysis model adjusting for age groups (18-39 years vs. 40-55 years). b Non-inferiority is supported if the upper bound of the 2-sided 95% CI is < 0.10 (+10%).

  16. Additional Endpoints (DV2-HBV-10)HEPLISAV administered on Weeks 0, 4, and 24 (Placebo)Engerix-B administered on Weeks 0, 4, 24 CI: Confidence Interval a Estimated response (proportion), their difference, and associated confidence intervals are based on a statistical analysis model adjusting for age groups (18-39 years vs. 40-55 years)

  17. Additional Endpoints (Study DV2-HBV-10)HEPLISAV administered on Weeks 0, 4, and 24 (Placebo)Engerix-B administered on Weeks 0, 4, 24

  18. Immunogenicity Conclusions (Study DV2-HBV-10) • HEPLISAV met pre-specified non-inferiority criteria for immunogenicity, as compared to the licensed active comparator hepatitis B vaccine, Engerix-B. • Findings for the mITT population paralleled that of the per protocol population.

  19. Study DV2-HBV-16 • 40-70 years of age • 32 sites in the U.S. and Canada • Randomization stratified by age: 40-49 yrs., 50-59 yrs, and 60-70 yrs • Randomization stratified by study site • Longer trial than DV2-HBV-10 (study duration of 52 weeks) • Evaluated lot consistency: • Subjects randomized to: • 1 of 3 consistency lots of HEPLISAV • An earlier lot of HEPLISAV, or • Engerix-B • Total of 2452 subjects randomized • n=1969 HEPLISAV • n=483 Engerix-B

  20. Primary Immunogenicity Endpoints and Criteria for Success • Co-primary immunogenicity endpoints: 1) Demonstration of HEPLISAV lot consistency between the 3 lots 2) Comparison of SPR between the 2 vaccine arms 8 weeks after the final active injection • Primary immunogenicity analysis: difference in SPR between the Engerix-B group at Week 32 (8 weeks after the last active dose) and HEPLISAV group at Week 12 (8 weeks after the last active dose) • Noninferiority between the 2 groups established if lower limit of the 2-sided 95% CI of the difference in SPR (SPR of 3 combined HEPLISAV lots at Wk 12 minus Engerix-B SPR at Wk 32) was > -10%

  21. Additional Immunogenicity Endpoints Studied in DV2-HBV-16 • Exploratory analyses: SPR and GMCs for HEPLISAV vs. Engerix-B at all other study time points (Weeks 4, 8, 12, 18, 24, 28, 32, 36, 44, and 52)

  22. Immunogenicity Analysis Populations • Noninferiority Per-Protocol Population: • Received 1 of 3 consistency lots of HEPLISAV or Engerix-B • Received all 3 protocol-specified study injections • No major protocol violations • Anti-HBsAg measurements and all injections obtained within pre-specified windows • Modified Intent-to-Treat Population (mITT): • Received at least 1 study injection • Had 1 post-baseline anti-HBsAg level

  23. Subject Demographics Summary • Similar demographic and baseline characteristics: • Most white (82%) or non-Hispanic/Latino (94%) • Mean age ~ 54 years • Percentage of females (52%) slightly higher than males (48%) • > 96% of subjects had anti-HBsAg levels < 5 mIU/mL (definition of seronegative) • Majority non-smokers (79%), non-diabetic (91- 92%) and non-obese (BMI ≤ 30 kg/m2, 56-57% for both treatment groups)

  24. Subject Disposition Summary • 2452 subjects enrolled • 1969 subjects assigned to HEPLISAV • 483 subjects assigned to Engerix-B • Non-inferiority PP population: • 1872 subjects (76.3% of randomized population) • 92.5% of all randomized subjects completed the study • Most common reason for subject discontinuation was “lost to follow-up” (3.8% of subjects)

  25. Primary Immunogenicity Endpoint Analysis (Study DV2-HBV-16)HEPLISAV administered on Weeks 0, 4, and 24 (Placebo)Engerix-B administered on Weeks 0, 4, 24 a Two-sided 95% CIs of the difference in seroprotection rates between the HEPLISAV group at 12 weeks and the Engerix-B group at 32 weeks was computed using the Newcombe score method with continuity correction. b Non-inferiority was supported if the lower limit of the two-sided 95% CI was greater than -10%

  26. Select SPRs by Visit: Per Protocol Population, Adults 40-70 Years of Age (Study DV2-HBV-16)

  27. Select GMCs by Visit: Per Protocol Population, Adults 40-70 Years of Age (Study DV2-HBV-16)

  28. Immunogenicity Conclusions (Study DV2-HBV-16) • HEPLISAV met pre-specified non-inferiority criteria for immunogenicity, as compared to the licensed active comparator hepatitis B vaccine, Engerix-B • Findings for the mITT population paralleled those of the per protocol population

  29. OVERALL CONCLUSIONS: Immunogenicity • For both phase 3 studies, the SPR following 2 doses of HEPLISAV was non-inferior to the SPR induced by 3 doses of Engerix-B • High seroprotection rates (≥ 90%) against hepatitis B were evident 8 weeks after the 2nd dose of HEPLISAV (Week 12)

  30. OVERALL CONCLUSIONS: Immunogenicity • Subgroup analyses for HEPLISAV immunized subjects did not reveal clinically significant differences between antibody responses in younger and older subjects, or between males and females • Conclusions could not be drawn regarding differences among ethnic and racial subgroups, although SPRs were similar among all ethnic groups examined

  31. VRBPAC: HEPLISAV BACK-UP SLIDES

  32. Comparison of SPRs: Pooled mITT for DV2-HBV-10 and 16, compared with Engerix-Bb, TWINRIXb and HAVRIX/Engerix-BbSPR at Weeks 4, 8, and 28 for HEPLISAV compared with Engerix-B: CI: Confidence Interval, NA: Not available in the label. a Estimated response (proportion), their difference, and associated confidence intervals are based on a statistical analysis model adjusting for age groups (18-39 years vs. 40-55 years) b Data taken from the Engerix-B and TWINRIX labels; SPR represents that against hepatitis B surface antigen. cSPR determined using the Ortho Vitros ECi Chemiluminescence Assay cSPR determined using the AxSYM AUSAB Microparticle Enzyme Immunoassay (EIA)

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