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

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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

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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

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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

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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.

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

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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

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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

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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

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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

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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)

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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

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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)

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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

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

HEPLISAV

SPR (%)

(n/N)

Engerix-B

SPR (%)

(n/N)

Estimated Difference in SPRa

(Engerix-B-HEPLISAV)

(95% CI)

Non-inferiority

Criteria Met?b

(Yes/No)

95.0 %(12 weeks)

(1479/1556)

81.1 %(28 weeks)

(432/533)

-13.9

(-17.6, -10.6)

Yes

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/mLa 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%).

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Additional Endpoints (DV2-HBV-10)

HEPLISAV administered on Weeks 0, 4, and 24 (Placebo)Engerix-B administered on Weeks 0, 4, 24

Visit HEPLISAVSPR (%)

Engerix-B

SPR (%)

Estimated Difference in SPRa

(Engerix-B – HEPLISAV (95% CI)

Week 4 23.6% 4.0% -19.7 (-22.4, -16.8)

Week 8 88.5 % 26.5 % -62.1 (-66.0, -57.9)

Week 12 95.0% 22.6% -72.5 (-76.0, -68.6)

Week 24 98.6% 32.5% -65.8 (-69.7, -61.6)

Week 28 97.9% 81.1% -16.8 (-20.4, -13.6)

CI: Confidence Intervala 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)

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

Visit HEPLISAV (N=1557)

GMC (mIU/mL), 95%CI

Engerix-B (N=533)

GMC (mIU/mL), 95%CI

Week 4 5.5 (5.1, 5.9) 2.9 (2.8, 3.1)

Week 8 81.5 (75.1, 88.5) 6.4 (5.6, 7.4)

Week 12 136.9 (127.5, 146.8) 5.5 (4.9, 6.2)

Week 24 342.5 (320.2, 366.5) 7.2 (6.3, 8.2)

Week 28 320.0 (298.2, 343.3) 348.2 (265.9, 455.9)

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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.

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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

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Primary Immunogenicity Endpoints and Criteria for Success

Co-primary immunogenicity endpoints:

1) Demonstration of HEPLISAV lot consistency between the 3 lots2) 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%

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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)

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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

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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)

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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)

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

Visit HEPLISAV

SPR (%)

(n/N)

Engerix-B

SPR (%)

(n/N)

Estimated Difference in

SPRa

(HEPLISAV-Engerix-B)

(95% CI)

Non-inferiority

Criteria Met?b

(Yes/No)

8 Weeks after last dose

90.0 %(Week 12)

(1011/1123)

70.5 %(Week 32)

(253/359)

19.6%

(14.7%, 24.7%) Yes

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%

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

Visit HEPLISAV SPR

(95 %CI)

Engerix-B SPR

(95% CI)

Week 4 19.9% (17.6%, 22.3%) 4.5% (2.6%, 7.1%)

Week 8 76.6% (74.0%, 79.0%) 20.3% (16.3%, 24.9%)

Week 12 90.0% (88.1%, 91.7%) 17.0% (13.3%, 21.3%)

Week 28 94.8% (93.4%, 96.1%) 72.8% (67.9%, 77.4%)

Week 32 94.8% (93.4%, 96.1%) 70.5% (65.5%, 75.1%)

Week 52 91.9% (90.1%, 93.5%) 59.0% (53.7%, 64.2%)

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

Visit HEPLISAV GMC

(95 %CI)

Engerix-B GMC(95% CI)

Week 4 1.3 (1.1, 1.6) 0.2 (0.2, 0.3)

Week 8 41.5 (36.1, 47.6) 0.9 (0.7, 1.2)

Week 12 93.0 (82.9, 104.2) 0.8 (0.6, 1.1)

Week 28 232.0 (209.2, 257.2) 88.5 (59.4, 131.9)

Week 32 222.3 (200.3, 246.7) 61.4 (41.7, 90.5)

Week 52 150.7 (134.8, 168.5) 19.5 (13.5, 28.1)

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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

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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)

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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

VRBPAC: HEPLISAV

BACK-UP SLIDES

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Comparison of SPRs: Pooled mITT for DV2-HBV-10 and 16, compared with Engerix-Bb, TWINRIXb and HAVRIX/Engerix-Bb

SPR at Weeks 4, 8, and 28 for HEPLISAV compared with Engerix-B:

Visit HEPLISAVc

SPR (%)

Engerix-Bc

SPR (%)

Engerix-Bd

(Label)

SPR (%)

TWINRIXd

(Label)

SPR (%)

HAVRIX and Engerix-Bd

(Label)

SPR (%)

Week 4 21.8% 4.2% NA 17.9% 7.5%Week 8 81.4 % 23.8 % NA 61.2% 50.4%Week 28 96.2% 76.7% 96.0% 95.1% 92.2%

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 AssaycSPR determined using the AxSYM AUSAB Microparticle Enzyme Immunoassay (EIA)

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