1 vaccines and related biological products advisory committee meeting hepatitis b vaccine...

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Vaccines and Related Biological Products Advisory Committee Meeting

Hepatitis B Vaccine (Recombinant), Adjuvanted (HEPLISAV):

Review of Safety

Lorie Smith, M.D., M.H.S.FDA/CBER/OVRR/DVRPA

November 15, 2012

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Overview

Discussion of safety data from Phase 3 trials DV2-HBV-10 and DV2-HBV-16

Discussion of key points from integrated analysis of safety in Phase 3 and supportive trials

Safety Summary Pharmacovigilance plan proposed by

Dynavax

3

Safety Population

Studies Total N Number of HEPLISAV Recipients

Number of ENGERIX-B

Recipients

Phase 3

Trials

4864 3777 1087

DV2-HBV-10 2415 1809 606

DV2-HBV-16 2449 1968 481

Supportive Trials

981 648 333

Total 5845 4425 1420

4

Safety Follow-Up Periods Phase 3 Trials (HEPLISAV N=3777, ENGERIX-B N=1087)

AE follow-up period: 28 weeks SAE follow-up period:

DV2-HBV-10: 28 weeks DV2-HBV-16: 52 weeks

Supportive Trials (HEPLISAV N=648, ENGERIX-B N=333) Controlled Studies

AE follow-up period: 4-28 weeks SAE follow-up period: 50-60 weeks

Uncontrolled Studies AE follow-up period:12-62 weeks SAE follow-up period: 28-62 weeks

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Phase 3 Trials:DV2-HBV-10 and DV2-HBV-16

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DV2-HBV-10: Safety Objective

Primary Safety Objective: To demonstrate safety and tolerability of vaccination with HEPLISAV when administered to adolescent and adult subjects

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DV2-HBV-10: Safety Population

Safety population: all subjects who received ≥1 study injection and had any post-baseline safety data

2415 adults and 13 adolescents were included in the safety population HEPLISAV: 1809 adults, 11 adolescents ENGERIX-B: 606 adults, 2 adolescents

8

DV2-HBV-10: Safety Assessments

Safety assessments and evaluation period Solicited reactions: 7 days post injection Adverse events (AEs) & serious adverse

events (SAEs): 28 weeks 24 weeks following last active injection of

HEPLISAV

Anti-nuclear antibody (ANA) & anti-double stranded DNA (anti-ds DNA): baseline and 28 weeks

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DV2-HBV-10: Solicited Local ReactionsDose 1

HEPLISAV

n=1809

Dose 1

ENGERIX-B

n=606

Dose 2

HEPLISAV

n=1797

Dose 2

ENGERIX-B

n=604

Pain 697

(38.5%)

203

(33.5%)

624

(34.7%)

150

(24.8%)

Redness 75

(4.1%)

3

(0.5%)

53

(2.9%)

6

(1.0%)

Swelling 41

(2.3%)

4

(0.7%)

27

(1.5%)

3

(0.5%)

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DV2-HBV-10: Solicited Systemic Reactions

Dose 1

HEPLISAV

n=1809

Dose 1

ENGERIX-B

n=606

Dose 2

HEPLISAV

n=1797

Dose 2

ENGERIX-B

n=604

Fatigue 315

(17.4%)

101

(16.7%)

248

(13.8%)

73

(12.1%)

Headache 304

(16.8%)

117

(19.3%)

229

(12.7%)

75

(12.1%)

Malaise 166

(9.2%)

54

(8.9%)

137

(7.6%)

39

(6.5%)

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DV2-HBV-10: Unsolicited Adverse Events

HEPLISAV 60.5% of subjects reported ≥ 1 unsolicited AE 10.6% of subjects reported a severe event

ENGERIX-B 62.0% of subjects reported ≥ 1 unsolicited AE 14.4% of subjects reported a severe event

Specific AEs discussed in the context of the ISS

12

DV2-HBV-10: Deaths and SAEs

Deaths: none reported for the 28 week duration of the trial

Nonfatal SAEs All SAEs occurred in subjects ≥ 18 years old 1.5% of HEPLISAV recipients and 2.1% of ENGERIX-

B recipients reported ≥ 1 SAE 3 SAEs were identified as autoimmune AEs and

will be discussed here Other specific SAEs will be discussed in the

context of the ISS

13

DV2-HBV-10: Autoimmune SAEs

HEPLISAV Subject 24057 - Cytoplasmic anti-neutrophil

cytoplasmic antibody (c-ANCA) positive vasculitis (Wegener’s granulomatosis)

Subject 11168 - Guillain-Barré syndrome

ENGERIX-B Subject 06083 - Perinuclear anti-neutrophil

cytoplasmic antibodies (p-ANCA) positive vasculitis

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DV2-HBV-10:Wegener’s Granulomatosis Wegener’s granulomatosis (HEPLISAV)

Subject 24057 - 55 year old female with no significant past medical history (PMHx)

Widespread urticaria 18 days after injection 1 Received injection 2 as scheduled Recurrent sinusitis began ~2.5 months after injection 1 Pulmonary infiltrates, pleural effusions & glomerulonephritis

approximately 7 months after injection 1 Serologic testing for ANCA yielded positive c-ANCA Wegener’s granulomatosis diagnosed

Received treatment with corticosteroids and cyclophosphamide Determined clinically stable 4 months after diagnosis Investigator’s assessment: possibly related to study treatment

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DV2-HBV-10: Wegener’s Granulomatosis

Serum retrospectively analyzed for ANCA Screening visit: ANCA negative 4 weeks after Dose 1: Protein 3 (PR3) ANCA weakly positive 8 weeks after Dose 1, 4 weeks after Dose 2: PR3 ANCA

weakly positive 12 weeks after Dose 1, 8 weeks after Dose 2: PR3 ANCA

positive 23 weeks after Dose 1, 19 weeks after Dose 2: PR3 ANCA

strongly positive 28 weeks after Dose 1, 24 weeks after Dose 2: PR3 ANCA

strongly positive

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DV2-HBV-10: Guillain-Barré Syndrome

Guillain-Barré syndrome (HEPLISAV) Subject 11168 - 36 year old female with a PMHx of

splenectomy Received inactivated influenza vaccine 105 days after

HEPLISAV injection 2 Five days later developed weakness

Progressed to respiratory failure Diagnosed as GBS

Course complicated by papillary carcinoma of the thyroid and bilateral pulmonary emboli

Investigator’s assessment: probably not related to study treatment

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DV2-HBV-10: p-ANCA + Vasculitis p-ANCA positive vasculitis (ENGERIX-B)

Subject 06083 - 44 year old female with PMHx that included mixed connective tissue disease (MCTD), osteoarthritis, food allergy & headache

Fever and malaise 3 months after 2nd injection of ENGERIX-B

127 days after 2nd injection pulmonary hemorrhage, positive p-ANCA leading to diagnosis

History of MCTD undisclosed at enrollment Baseline ANA >1:5120; ANCA testing of banked

serum negative until time of diagnosis Investigator’s assessment: not related to study

treatment

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DV2-HBV-10: Laboratory Investigations

ANA (baseline, Week 28) Most subjects had ANA titers < 1:160 at baseline

(HEPLISAV 89.3%, ENGERIX-B 91.9%) and at Week 28 (HEPLISAV 89.3%, ENGERIX-B 91.4%)

ANA results were comparable among treatment groups for each serial dilution

2.9% of HEPLISAV recipients and 3.3% of ENGERIX-B recipients experienced an increase in ANA titer

Most subjects experiencing an increase had a 1 dilution increase

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DV2-HBV-10: Laboratory Investigations

Anti-ds DNA (baseline, Week 28) 99.1% of HEPLISAV subjects and 98.8% of ENGERIX-B

subjects had negative anti-dsDNA at baseline 0.5% of subjects in each treatment group converted from a

negative result at baseline to a positive result at Week 28

ANCA Evaluated retrospectively on banked serum from 1780

HEPLISAV recipients and 596 ENGERIX-B recipients 3 (0.2%) of HEPLISAV recipients and 2 (0.3%) of ENGERIX-

B recipients had positive ANCA by ELISA None of these subjects had positive ANCA by

immunofluorescence

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DV2-HBV-10: Summary Higher rate of injection site reactions in HEPLISAV group

Mostly mild Similar rates of solicited systemic reactions, unsolicited

AEs and SAEs No clinically important differences in ANA titers or anti-

dsDNA levels 2 cases of ANCA-positive vasculitis

Subsequent studies contained algorithm to capture Autoimmune AEs (AIAEs) in which suspected AIAEs were referred to a Safety Evaluation & Adjudication Committee (SEAC)

AEs of special interest (AESI): selected neuroinflammatory, musculoskeletal, gastrointestinal, metabolic, skin & AI diseases were also captured in subsequent studies

Trial DV2-HBV-16

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DV2-HBV-16: Safety Objectives

Safety Objectives Demonstrate safety of HEPLISAV in healthy

subjects 40-70 years of age Compare the safety profile of HEPLISAV to

that of ENGERIX-B in this population

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DV2-HBV-16: Safety Population

Safety population Received ≥ 1 study injection Had any post-baseline safety data

2449 subjects 40-70 years of age HEPLISAV: n = 1968

Consistency Lots: n = 1439 Lot TDG006: n = 529

ENGERIX-B: n = 481

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DV2-HBV-16: Safety Assessments

Safety assessments and evaluation period Solicited reactions: 7 days after each injection AEs: 28 weeks after injection 1 (24 weeks after last

active dose of HEPLISAV) SAEs/AESIs/potential AIAEs: 52 weeks after injection

1 (48 weeks after last active dose of HEPLISAV) AIAEs to SEAC for adjudication

Serum chemistry/hematology: baseline, 4, 8, 24, 28 weeks after injection 1

ANA, anti-dsDNA: baseline, 52 weeks

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DV2-HBV-16: Solicited Local ReactionsDose 1

HEPLISAV

Consistency Lots

Dose 1

HEPLISAV

Lot TDG006

Dose 1

ENGERIX-B

Dose 2

HEPLISAV

Consistency

Lots

Dose 2

HEPLISAV

Lot TDG006

Dose 2

ENGERIX-B

n=1427 n=525 n=477 n=1398 n=507 n=464

Redness 244

(17.1%)

103

(19.6%)

72

(15.1%)

150

(10.7%)

84

(16.6%)

45

(9.7%)

Swelling 123

(8.6%)

49

(9.3%)

38

(8.0%)

87

(6.2%)

37

(7.3%)

26

(5.6%)

Pain 319

(22.4%)

143

(27.2%)

88

(18.4%)

314

(22.5%)

120

(23.7%)

74

(15.9%)

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DV2-HBV-16: Solicited Systemic Reactions

Dose 1

HEPLSIAV

Consistency Lots

Dose 1

HEPLISAV

Lot

TDG006

Dose 1

ENGERIX-B

Dose 2

HEPLISAV

Consistency Lots

Dose 2

HEPLISAV

Lot

TDG006

Dose 2

ENGERIX-B

n=1427 n=525 n=477 n=1398 n=507 n=464

Malaise 108

(7.6%)

43

(8.2%)

41

(8.6%)

92

(6.6%)

42

(8.3%)

33

(7.1%)

Headache 169

(11.8%)

61

(11.6%)

57

(11.9%)

114

(8.2%)

41

(8.1%)

44

(9.5%)

Myalgia 116

(8.1%)

50

(9.5%)

46

(9.6%)

80

(5.7%)

42

(8.3%)

37

(8.0%)

Fatigue 178

(12.5%)

68

(13.0%)

61

(12.8%)

147

(10.5%)

58

(11.4%)

56

(12.1%)

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DV2-HBV-16: Unsolicited Adverse Events

HEPLISAV Consistency Lots 25.2% of subjects reported ≥ 1 unsolicited AE 4.5% of subjects reported a severe event

HEPLISAV Lot TDG006 25.1% of subjects reported ≥ 1 unsolicited AE 5.9% of subjects reported a severe event

ENGERIX-B 24.7% of subjects reported ≥ 1 unsolicited AE 5.8% of subjects reported a severe event

Specific AEs will be discussed in the context of the ISS

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DV2-HBV-16: Deaths and SAEs

Deaths HEPLISAV

46 yo male with no PMHx had fatal PE 46 days after the 2nd injection of Lot TDG006

Dynavax unable to obtain medical records

ENGERIX-B 64 yo male with PMHx that included hypertension

and gout hospitalized for acute myocardial infarction 43 days after 2nd injection. Died of cardiac arrest on 2nd day of hospitalization

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DV2-HBV-16: SAEs

Nonfatal SAEs Similar proportion of subjects in each group

reported ≥ 1 SAE HEPLISAV consistency lots: 3.4% Lot TDG006: 5.1% ENGERIX-B: 4.8%

Specific SAEs will be discussed in the context of the ISS

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DV2-HBV-16: AIAEs

9 events in HEPLISAV recipients initially identified by the investigator as potential AIAEs 2 subsequently determined not to be AI in nature

7 considered potential AIAEs 5 confirmed AIAEs by the SEAC

2 individuals with evidence of pre-existing disease when banked baseline serum evaluated

3 determined to be new-onset AIAEs

DV2-HBV-16: AIAEsAge/ Sex

Potential AIAE Days After

Dose 1

Days After

Dose 2

Related (Investigator)

AIAE (Investigator)

Related (SEAC)

AIAE (SEAC)

New

58y F Hypothyroidism 26-30 -2 - +2 Possibly Yes No Yes Yes

53y F Hypothyroidism 58 29 Not Yes No Yes Yes

70y M Vitiligo 29 1 Possibly Yes No Yes Yes

59 y F Hypothyroidism 218 187 Not Yes No Yes No

57y M Hypothyroidism 52 33 Possibly Yes No Yes No

62y M E. nodosum 47 19 Possibly Yes Yes No -

60y M Bell’s palsy 298 270 Not Yes No No -

43y F Hypothyroidism 196 168 Possibly Y,N No No -

52y F Microscopic Colitis

3 N/A Not Y,N No No -

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DV2-HBV-16: PEAI

Subjects with pre-existing AI disorders (PEAI) 30 subjects with PEAI inadvertently enrolled:

15 randomized to HEPLISAV consistency lots, 8 to Lot TDG006, 7 to Engerix-B

Overall, AEs & SAEs occurred with higher frequency in PEAI subgroup than general study population (60% versus 51.5%)

Frequency of AEs & SAEs among PEAI similar among treatment groups

33

DV2-HBV-16: Laboratory Investigations

Hematology & serum chemistry performed at Baseline, Weeks 4, 24, 28 Similar across treatment groups and did not

change significantly from baseline Anti-dsDNA evaluated at Baseline, Week

52 Most subjects had negative results at baseline

(HEPLISAV consistency lots: 98.5%, Lot TDG006 98.1%, ENGERIX-B: 97.3%)

Proportion converting from negative to positive was similar between groups

34

DV2-HBV-16: Laboratory Investigations

ANA evaluated at Baseline, Week 52 Most subjects had negative ANA (<1:160) at

baseline (HEPLISAV consistency lots: 95.6%, Lot TDG006: 94.3%, ENGERIX-B: 93.1%)

Similar proportion of subjects in each treatment group converted from a negative baseline titer to a positive titer at Week 52

Similar proportion of subjects with positive baseline titers had increased titers at Week 52 in each treatment group

35

DV2-HBV-16: Summary

Higher rate of injection site reactions in HEPLISAV recipients

Similar rates of solicited systemic reactions, unsolicited AEs and SAEs

3 (0.2%) HEPLISAV recipients and 0 Engerix-B recipients in Study DV2-HBV-16 reported SEAC- confirmed new-onset AIAEs Deemed not related to vaccination by SEAC

No clinically important differences noted in laboratory parameters

Integrated Summary of Safety: Key Points

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ISS Study Population

Studies Total N Number of HEPLISAV Recipients

Number of ENGERIX-B

Recipients

Phase 3

Trials

4864 3777 1087

DV2-HBV-10 2415 1809 606

DV2-HBV-16 2449 1968 481

Supportive Trials

981 648 333

Total 5845 4425 1420

38

ISS Study Population

13 additional subjects age 11-17 years participated in Study DV2-HBV-10

The safety data from these individuals were also evaluated as part of a comprehensive safety review

39

Safety Follow-Up Periods Phase 3 Trials (HEPLISAV N=3777, ENGERIX-B N=1087)

AE follow-up period: 28 weeks SAE follow-up period:

DV2-HBV-10: 28 weeks DV2-HBV-16: 52 weeks

Supportive Trials (HEPLISAV N=648, ENGERIX-B N=333) Controlled Studies

AE follow-up period: 4-28 weeks SAE follow-up period: 50-60 weeks

Uncontrolled Studies AE follow-up period:12-62 weeks SAE follow-up period: 28-62 weeks

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Demographics of Safety Population

Baseline characteristics of subjects receiving HEPLISAV and Engerix-B do not suggest selection bias based on age, sex, race or Hispanic ethnicity 83.0% of HEPLISAV recipients and 72.6% of

ENGERIX-B recipients were of white race 96.2% of HEPLISAV recipients and 95.9% of

ENGERIX-B recipients were of non-Hispanic ethnicity 56.0% of HEPLISAV recipients and 58.4% of

ENGERIX-B recipients were 40-55 years old

ISS: Safety Results

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ISS: Laboratory Investigations

Laboratory Investigations Hematology, serum chemistries, ANA, anti-

dsDNA, ANCAs*, complement components C3 & C4, erythrocyte sedimentation rate (ESR) and urinalyses were evaluated

No clinically significant trends were identified post-vaccination

* Retrospectively evaluated in Studies DV2-HBV-10 & DV2-HBV-14

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Deaths 2 deaths in Study DV2-HBV-16, no other

deaths reported

Non-fatal SAEs All SAEs in adult subjects ≥ 18 years of age 2.7% of HEPLISAV recipients and 3.7% of

Engerix-B recipients reported ≥ 1 SAE

ISS: Deaths & SAEs

44

ISS: Unsolicited AEs

AEs Overall incidence similar between treatment

groups (HEPLISAV: 58.1%, Engerix-B: 61.2%)

Most mild-moderate in intensity

45

Pulmonary Emboli

Numerical imbalance between incidence of PE: HEPLISAV: n=5 (0.1%); Engerix-B 0 1 case was fatal 4/5 occurred in individuals with underlying

predisposition 32 y F, obese, smoker, oral contraceptives, +anti-

phospholipid antibodies 26y M, ruptured anterior cruciate ligament 61y M, recent prolonged road trip 36 y F, hospitalized with GBS

46

Other Thrombotic Events

Post-operative deep vein thrombosis (DVT) HEPLISAV: n=1, ENGERIX-B: n=1

Superficial thrombophlebitis HEPLISAV n=1

Thrombosis ENGERIX-B n=2

Total thrombotic SAEs & AEs HEPLISAV: 7 (0.2%), ENGERIX-B: 3 (0.2%)

47

ISS: AIAEs & AESIs (Dynavax Analysis)

AIAEs Collected prospectively only for study DV2-HBV-16,

so no integrated analysis

AESIs: Dynavax searched safety database for selected neuroinflammatory, musculoskeletal, gastrointestinal, metabolic, skin & autoimmune disorders from list of AEs used in other trials HEPLISAV

0.2% of subjects reported AESIs

ENGERIX-B 0.4% of subjects reported AESIs

48

AEs of Potential Autoimmune Origin (FDA Analysis)*

FDA analysis of SAEs, AESIs, AIAEs treated with immunosuppressive medications HEPLISAV 0.2%, ENGERIX-B 0.2%

*Includes AIAEs & AESIs evaluated by Dynavax

FDA Analysis: SAEs, AESIs, AIAEs Treated with Immunosuppressive Therapy

AE Arm Days after Last

Active Injection

PMH Treatment Background incidence/yr

Tolosa-Hunt HEPLISAV 165 No Steroids 1/1,000,000

Wegener’s HEPLISAV 72 No Steroids, Cyclophosphamide 7.4-12.2/1,000,000

E. Nodosum HEPLISAV 19 No Steroids 1-5/100,000

Bell’s Palsy HEPLISAV 15 No Steroids 13-34/100,000

Bell’s Palsy HEPLISAV 270 No Steroids 13-34/100,000

Uveitis HEPLISAV 30 No Steroids 20-52/100,000

Vitiligo HEPLISAV 1 Yes* Topical steroids, Elidel 0.14 - 8.8/100

SLE HEPLISAV 84 Yes Hydroxychloroquine Exacerbation

RA HEPLISAV 5 Yes Etoricoxib, Diclofenac Exacerbation

RA HEPLISAV 22 Yes Rofecoxib, Ibuprofen Exacerbation

M. Colitis HEPLISAV 3 Yes Budesonide Exacerbation

* PMH of another autoimmune disease49

FDA Analysis: SAEs, AESIs, AIAEs Treated with Immunosuppressive Therapy

AE Arm Days after Last Active Injection

PMH Treatment Background Incidence/yr

p-ANCA

Vasculitis

ENGERIX-B 126 Yes* Steroids,

Cyclophosphamide

7.7-12.6/

1,000,000

Bell’s palsy ENGERIX-B 121 No Steroids 13-34/100,000

RA ENGERIX-B 20 Yes** Steroids, meloxicam

41/100,000

RAD*** ENGERIX-B 56 No Steroids N/A

*PMH of another AI disease** PMH of symptoms consistent with the disease***SAE of bronchial hyperreactivity for which Churg-Strauss workup was performed that was negative

51

AEs of Potential Autoimmune Origin (FDA Analysis)*

Thyroid events were included in analysis of AEs of potential AI origin Most common cause of hypothyroidism in iodine

sufficient countries is autoimmune thyroiditis (Hashimoto’s thyroiditis)

Most common cause of hyperthyroidism is Grave’s disease/Basedow’s disease

Can present as goiter, hypothyroidism or hyperthyroidism

An FDA analysis of all thyroid AEs will be discussed here

*Includes AIAEs & AESIs evaluated by Dynavax

52

ISS: Summary of Thyroid Events

Overall incidence of thyroid diseases reported as AEs HEPLISAV: 19 events/16 subjects (0.4%) ENGERIX-B: 2 events in 2 subjects (0.1%)

Relative Risk* 2.6. 95% confidence interval [CI] (0.7, 10.0)

All thyroid diseases & thyroid lab results reported as AEs HEPLISAV: 20 events in 17 subjects (0.4%) ENGERIX-B: 3 events in 3 subjects (0.2%)

Relative Risk* 1.8, 95% CI (0.6, 5.8)

*Relative Risk (HEPLISAV/ENGERIX-B)

Age/ Sex

AE Days After Dose 1

Days After Dose 2

Days After Dose 3

PMH Arm

45y M Low TSH 44 17 N/A Symptoms HEPLISAV

40y F Hyperthyroidism 30-60 1-31 N/A Yes HEPLISAV

45y F Hypothyroidism 173 145 0 Yes/ ↑Dose HEPLISAV

59y F Hypothyroidism 218 187 N/A Yes (labs) HEPLISAV

57y M Hypothyroidism 52 33 N/A Yes (labs) HEPLISAV

24y F Hyperthyroidism 36 8 N/A No HEPLISAV

53y F Hypothyroidism

Hyperthyroidism

69

154

42

127

N/A

N/A

No HEPLISAV

24y F Thyroiditis 73 45 N/A No HEPLISAV

32y F Goiter 32 7 N/A No HEPLISAV

48y F Hypothyroidism 48 34 N/A No HEPLISAV

41y F Basedows Disease 72 43 N/A No HEPLISAV

58y F Hypothyroidism 26-30 -2-+2 N/A No HEPLISAV

53y F Hypothyroidism 58 29 N/A No HEPLISAV

43y F Hypothyroidism 196 168 N/A No HEPLISAV

30y F Basedows Disease 85 57 N/A Yes ENGERIX-B

49y F Decreased T4 22 N/A N/A No ENGERIX-B

47y M Hypothyroidism ~150 ~120 N/A No ENGERIX-B

Age/ Sex

AE Days After Dose 1

Days After Dose 2

Days After Dose 3

Days After Dose 4

PMH Arm

40y F Thyroid Disorder

Hyperthyroidism

Hypothyroidism

109 45 N/A N/A Yes HEPLISAV

22y M Enlarged

Thyroid

462 436 238 N/A No HEPLISAV

38y F Multinodular

Goiter

3 N/A N/A N/A Unclear HEPLISAV

66y F Diffuse Nontoxic Goiter*

7 N/A N/A N/A Yes HEPLISAV

42y M Thyroid Mass* 211 191 166 113 No HEPLISAV

*Not considered autoimmune in nature

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Safety Summary

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ISS: Summary

Review of local & systemic solicited AEs, deaths, & laboratory investigations did not reveal any clinically significant differences between recipients of HEPLISAV and ENGERIX-B

Nonfatal SAEs occurred with similar incidence between groups

57

ISS: Summary

Numerical imbalance in incidence of PEs

Overall incidence of thrombotic events similar between HEPLISAV and ENGERIX-B recipients

58

ISS: Summary

AIAEs were evaluated prospectively in Study DV2-HBV-16 (Dynavax) 5 AIAEs were identified, 2 of which occurred

in subjects with evidence of pre-existing disease

AESIs were reviewed for all trials (Dynavax) By selected MedRA preferred term (PT), the

incidence of AESIs was similar between groups

59

ISS: Summary

FDA analysis of other events of potential AI origin Comprehensive evaluation of all thyroid-

related AEs potentially representing autoimmune events Reported in a higher proportion of

HEPLISAV recipients Relative Risk confidence intervals include 1

AEs requiring immunosuppressive therapy occurred with similar incidence between HEPLISAV and ENGERIX-B recipients

60

ISS: Summary

Rare serious events reported among HEPLISAV recipients Wegener’s granulomatosis Tolosa-Hunt syndrome Guillain-Barré syndrome

Rare serious events reported among ENGERIX-B recipients p-ANCA positive vasculitis

61

ISS: Limitations Autoimmune diseases occur with relatively rare

incidence in the general population Often insidious in onset Early symptoms often non-specific Making assessment of causality with vaccine receipt

difficult Large sample sizes necessary for statistically robust

assessment of risk For relatively infrequent AEs, statistical

variability in observed rates among 4425 HEPLISAV and 1420 ENGERIX-B recipients limits the ability to draw firm conclusions about vaccine attribution

62

Post-Licensure Pharmacovigilance PlanProposed by Dynavax

63

Pharmacovigilance Plan

Routine Surveillance Spontaneous AE report collection, follow-up &

assessment Review of medical literature & safety

information from other sources Safety signal identification & evaluation Close monitoring for AESIs Reports of exposure to HEPLISAV during

pregnancy will be followed to ascertain outcome

64

Pharmacovigilance Plan Open-label, prospective, observational matched

cohort study in 5000 individuals initiating vaccination with HEPLISAV and 15000 individuals initiating vaccination with a non-HEPLISAV Hepatitis B vaccine or secondarily any other vaccine

12 month safety evaluation Dynavax proposes data to be available 5 years

after approval If necessary, additional cohort(s) will be followed

for refined hypothesis testing

65

Questions to the Committee

1. Are the immunogenicity data adequate to support the effectiveness of HEPLISAV for the prevention of hepatitis B virus infection in adults 18 through 70 years of age?

Please vote Yes or No.

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Questions to the Committee

2. Are the available data adequate to support the safety of HEPLISAV when administered to adults 18 through 70 years of age?Please vote Yes or No.

If yes, is the proposed pharmacovigilance plan adequate to further evaluate the safety of HEPLISAV post-licensure?

If no, please discuss what additional studies (pre- & post-licensure) are needed to further evaluate the safety of HEPLISAV.