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Overview

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

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Overview

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

  2. 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

  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

  9. DV2-HBV-10: Solicited Local Reactions

  10. DV2-HBV-10: Solicited Systemic Reactions

  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

  14. 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 HEPLISAVinjection 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. Trial DV2-HBV-16

  22. 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

  24. 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

  25. DV2-HBV-16: Solicited Local Reactions

  26. DV2-HBV-16: Solicited Systemic Reactions

  27. 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

  31. DV2-HBV-16: AIAEs

  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

  36. Integrated Summary of Safety: Key Points

  37. ISS Study Population

  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

  41. ISS: Safety Results

  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. ISS: Deaths & SAEs • 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

  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

  49. FDA Analysis: SAEs, AESIs, AIAEs Treated with Immunosuppressive Therapy * PMH of another autoimmune disease

  50. FDA Analysis: SAEs, AESIs, AIAEs Treated with Immunosuppressive Therapy *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

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