1 vaccines and related biological products advisory committee meeting hepatitis b vaccine...
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1
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
5
Phase 3 Trials:DV2-HBV-10 and DV2-HBV-16
6
DV2-HBV-10: Safety Objective
Primary Safety Objective: To demonstrate safety and tolerability of vaccination with HEPLISAV when administered to adolescent and adult subjects
7
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%)
10
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%)
11
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
15
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
16
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
23
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
28
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
29
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
30
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 -
32
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
36
37
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
40
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
41
42
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
43
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
55
Safety Summary
56
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.
66
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.