Presentation is loading. Please wait.

Presentation is loading. Please wait.

A-1 Q-Pan H5N1 Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted Donna Boyce Head North America, Global Regulatory Affairs GlaxoSmithKline Vaccines.

Similar presentations


Presentation on theme: "A-1 Q-Pan H5N1 Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted Donna Boyce Head North America, Global Regulatory Affairs GlaxoSmithKline Vaccines."— Presentation transcript:

1 A-1 Q-Pan H5N1 Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted Donna Boyce Head North America, Global Regulatory Affairs GlaxoSmithKline Vaccines

2 A-2 Introduction Donna Boyce Head, North America Global Regulatory Affairs Immunogenicity & Effectiveness Bruce Innis, MD Vice President Vaccine Discovery and Development Safety Felix Arellano, MD Vice President Vaccines Clinical Safety and Pharmacovigilance ConclusionDonna Boyce GSK Presentation

3 A-3 BARDA / GSK Partnership: Develop & License Q-Pan H5N1 HHS Pandemic Influenza Plan encourages manufacturers to develop pandemic vaccines GSK / BARDA partnership to develop and submit for licensure H5N1 vaccine with antigen-sparing potential Vaccine will be distributed by US Government US Government will determine use of vaccine

4 A-4 Q-Pan H5N1 Desired Characteristics Acceptable reactogenicity and safety profile Rapid induction of protective immune responses in immunologically naïve persons Antigen-sparing Rapid production using existing facilities and processes

5 A-5 Q-Pan H5N1 Proposed Indication and Usage Intended for active immunization for the prevention of disease in persons 18 years of age and older who are at increased risk of exposure to the H5N1 influenza virus subtype contained in the vaccine 2-dose series (0.5 mL each) by intramuscular injection ~21 days interval between doses

6 A-6 FluLaval (Accelerated Approval) Quebec (Q) Q-Pan H5N1 Q-Pan H1N1 Fluarix (Traditional Approval) Dresden (D) D-Pan H5N1 D-Pan H1N1 Seasonal Pandemic Q-QIV D-QIV GSK’s Influenza Vaccines

7 A-7 Q-Pan H5N1 Registered in 30 Countries Q-Pan H5N1 Under Review Q-Pan H5N1

8 A-8 GSK’s H1N1 Pandemic Experience: Registered in > 50 Countries Worldwide Quebec & Dresden H1N1 Registrations > 90 Million Doses Administered

9 A-9 Q-Pan H5N1: Two Component Vaccine H5N1 Antigen Egg-based inactivated, split A/H5N1 influenza type A virus (A/Indonesia/5/2005) Manufactured in Quebec (Q) according to FluLaval® process AS03 Adjuvant System D, L-α-tocopherol, squalene & polysorbate 80 Manufactured in Belgium Final Vaccine Composition (0.5 mL dose) 10 doses per vial 3.75 µg HA per dose D,L-α-tocopherol (11.86 mg), squalene (10.69 mg) & polysorbate 80 (4.86 mg) 5 µg thimerosal per dose Mixed 1:1 Prior to Injection

10 A-10 Pathway for Accelerated Approval of Q-Pan H5N1 US Licensed Seasonal Influenza Vaccine Accelerated Approval Efficacy not yet confirmed Source FluLaval Pre-approval BLA 2013 During a Pandemic Timing Q-Pan H5N1 licensure approach: Accelerated Approval Safety Immunogenicity Q-Pan H5N1-001 Q-Pan H5N1-002 Effectiveness of Q-Pan H5N1 inferred when the efficacy of the seasonal confirmed FluLaval Q-QIV-006 Post-approval Work with US Gov’t to collect safety/effectiveness data with Q-Pan H5N1 CBER Guidance

11 A-11 Large and Comprehensive Development Program N =number of subjects receiving active or control vaccine (Total Vaccinated Cohort) ( ) =subjects receiving final formulation of vaccine (Q-Pan 3.75 µg HA + AS03 A ) or any formulation with AS03 for ISS Supportive H1N1 Effectiveness Studies Pivotal Studies N=5,341 (3,574) Supportive Dosing Interval and Booster Studies N=1,153 (431) Dose Finding Study N=400 (0) Q-Pan-009 Short Interval years Q-Pan-005 Long Interval ≥ 18 years Q-Pan-010 Boost years D-Pan H5N years Q-Pan-001 Dose Confirmation years Q-Pan-002 Safety, Consistency ≥ 18 years New Brunswick 6 mo-9 years Manitoba ≥ 6 months Canada Multi-Province ≥ 6 months Supportive Safety Summaries N=22,521 (16,160) H5N1 ISS-1 [2009] ≥ 18 years H5N1+H1N1 ISS-2 [2011] ≥ 18 years BLA Database Q-QIV-006 Absolute Vaccine Efficacy 3-8 years Q-Pan H1N1-035 Relative Vaccine Efficacy 6 mo-8 years Post-Licensure Commitment Key Supportive Data

12 A-12 Introduction Donna Boyce Head, North America Global Regulatory Affairs Immunogenicity & Effectiveness Bruce Innis, MD Vice President Vaccine Discovery and Development Safety Felix Arellano, MD Vice President Vaccines Clinical Safety and Pharmacovigilance ConclusionDonna Boyce GSK Presentation

13 A-13 Immunogenicity and Effectiveness Outline Rationale for addition of AS03 to Q-Pan H5N1 Q-Pan H5N1 immunogenicity data Clinical endpoint data from vaccines manufactured using Quebec processClinical endpoint data from vaccines manufactured using Quebec process

14 A-14 CBER Immunogenicity Criteria CBER’s Immune Response Thresholds Sero- conversion rate (SCR) Proportion with a 4-fold increase in HI titers (note: if < 1:10 at baseline, must increase to at least 1:40) LL 95% CI ≥18-64 years: 40%≥ 65 years: 30% Sero- protection rate (SPR) Proportion with HI titers ≥ 1:40 LL 95% CI ≥18-64 years: 70%≥ 65 years: 60% In some human challenge studies of seasonal influenza viruses, HI titers of ≥ 1:40 have been associated with protection from illness in up to 50% of subjects

15 A-15 A Pandemic Vaccine Optimally Should Be Effective at Antigen-Sparing Doses Licensed H5N1 vaccine (no adjuvant) at 90 µg HA x2 weakly immunogenic Whole virus adsorbed to aluminum  limited antigen-sparing AS03 –Amenable to stockpiling and surge production –Antigen-sparing relative to licensed vaccine –Enhanced immunologic priming after 1 dose –Strong homologous (and cross-reactive) responses to 2 doses Hehme et al., International Conference on Influenza Vaccines the World, October 2006, Vienna, Austria Garçon et al., Expert Rev. Vaccines 2012; 11(3), 349–366

16 A-16 AS03 Elicits an Enhanced, Transient, Local Innate Immune Response Co-injection of AS03 + antigen is necessary for effect Induces a transient innate immune response at the injection site and draining lymph nodes Accounts for –Injection site reactions –Potent humoral and cellular adaptive immune response Morel et al., Vaccine 2011; 29: Characterized in vivo in mice, ex vivo in human cells

17 A-17 Large and Comprehensive Development Program N =number of subjects receiving active or control vaccine (Total Vaccinated Cohort) ( ) =subjects receiving final formulation of vaccine (Q-Pan 3.75 µg HA + AS03 A ) or any formulation with AS03 for ISS Supportive H1N1 Effectiveness Studies Pivotal Studies N=5,341 (3,574) Supportive Dosing Interval and Booster Studies N=1,153 (431) Dose Finding Study N=400 (0) Q-Pan-009 Short Interval years Q-Pan-005 Long Interval ≥ 18 years Q-Pan-010 Boost years D-Pan H5N years Q-Pan-001 Dose Confirmation years Q-Pan-002 Safety, Consistency ≥ 18 years New Brunswick 6 mo-9 years Manitoba ≥ 6 months Canada Multi-Province ≥ 6 months Supportive Safety Summaries N=22,521 (16,160) H5N1 ISS-1 [2009] ≥ 18 years H5N1+H1N1 ISS-2 [2011] ≥ 18 years BLA Database Q-QIV-006 Absolute Vaccine Efficacy 3-8 years Q-Pan H1N1-035 Relative Vaccine Efficacy 6 mo-8 years Post-Licensure Commitment Key Supportive Data D-Pan H5N years D-Pan H5N years Q-Pan-001 Dose Confirmation years Q-Pan-001 Dose Confirmation years Q-Pan-002 Safety, Consistency ≥ 18 years Q-Pan-002 Safety, Consistency ≥ 18 years New Brunswick 6 mo-9 years New Brunswick 6 mo-9 years Manitoba ≥ 6 months Manitoba ≥ 6 months Canada Multi-Province ≥ 6 months Canada Multi-Province ≥ 6 months

18 A-18 Q-Pan H5N1 Immunogenicity Data

19 A-19 SCR (%) Post dose 1 Post dose µg 7.5µg 15µg 30µg 3.75µg + AS03 A 7.5µg + AS03 A 15µg + AS03 A 30µg + AS03 A Leroux-Roels et al., Lancet 2007; 370 (9587):580–89 D-Pan H5N1-007: Antigen Dose Selected for D-Pan Was Used for Q-Pan (Per Protocol Immunogenicity Cohort, Belgium, 2006) 50 subjects per group (18-60 yrs of age) CBER SPR Target

20 A-20 Q-Pan H5N1-001: To Confirm AS03 Benefit, Equivalence to D-Pan, and AS03 Dose (Total Vaccinated Cohort = 780 adults, USA/Canada, ) Q-Pan 3.75 µgN=78 Q-Pan 3.75 µg + AS03 A N=152 Q-Pan 3.75 µg + AS03 B N=150 D-Pan 3.75 µg + AS03 A N=151 D-Pan 3.75 µg + AS03 B N=149 Q-Pan 1.9 µg + AS03 A N=50 Q-Pan 1.9 µg + AS03 B N=50 Adjuvant benefit Immunogenicity equivalence If Q-Pan/AS03 groups have SPR ≥ 76%, enroll half dose groups

21 A-21 Q-Pan H5N1-001 Confirmed AS03 Benefit (SCR increase > 15%) (Per Protocol Immunogenicity Cohort) CBER SPR Target ΔSPR/SCR ~ 80% Langley et al., JID 2010; 201: Day 0Day 21Day 42 Q-Pan OnlyQ-Pan + AS03 A D-Pan + AS03 A Q-Pan + AS03 B D-Pan + AS03 B

22 A-22 Q-Pan H5N1-001 Confirmed AS03 Benefit (GMT increase > 2-fold) (Per Protocol Immunogenicity Cohort) Langley et al., JID 2010; 201: Day 0Day 21Day 42 GMT increase 43-fold Q-Pan OnlyQ-Pan + AS03 A D-Pan + AS03 A Q-Pan + AS03 B D-Pan + AS03 B

23 A-23 Q-Pan H5N1-001 Confirms Q-Pan Equivalence to D-Pan (GMT ratio within 0.67 – 1.5) (Per Protocol Immunogenicity Cohort) GMT ratio 0.94 (95% CI 0.75, 1.17) Langley et al., JID 2010; 201: Q-Pan OnlyQ-Pan + AS03 A D-Pan + AS03 A Q-Pan + AS03 B D-Pan + AS03 B

24 A-24 Q-Pan H5N1-001 Shows Good 1-Dose Priming (Per Protocol Immunogenicity Cohort) Anamnestic response requires AS03 Langley et al., JID 2010; 201: Q-Pan OnlyQ-Pan + AS03 A D-Pan + AS03 A Q-Pan + AS03 B D-Pan + AS03 B

25 A-25 Q-Pan H5N1-001 Showed Only 3.75 µg + AS03 A Preserved Immunogenicity for Older Adults (Post hoc analysis) Langley et al., JID 2010; 201: μg + AS03 A 3.75 μg + AS03 B 1.9 μg + AS03 A 1.9 μg + AS03 B 96.3% 98.4% 86.2% 96.0% 95.8% 92.3% 75.0% 92.6% GMT (95% CI) Day 42 Immunogenicity (Homologous HI) as GMT and SPR GMT and/or SPR decreased GMT and SPR preserved

26 A-26 Q-Pan H5N1-002: To Confirm Lot Consistency and Immunogenicity (Safety) for Adults of All Ages (Total Vaccinated Cohort = 4561, USA/Canada, 2008) Ag lot A + AS03 lot 1 N=570, yrs Ag lot B + AS03 lot 2 N=568, yrs Ag lot C + AS03 lot 3 N=569, yrs Placebo (PBS) N=568, yrs Ag lot ABC + AS03 lot 1 N= 597, yrs Placebo (PBS) N=200, yrs Ag lot ABC + AS03 lot 1 N=1118, > 64 yrs Placebo (PBS) N=371, > 64 yrs Immunogenicity: SCR & SPR ages Lot to lot consistency: GMT ratio ages Healthy Stable health Immunogenicity: SCR & SPR ages > 64

27 A-27 Q-Pan H5N1-002 Demonstrated Good Immunogenicity Regardless of Age (Per Protocol Immunogenicity Cohort) Immunogenicity (Homologous HI) as Day 0 and 42 GMTs and SCRs Day 0Day 42Day 0Day 42 All lotsPlacebo ≥ 75 N=119 72% SCR N=396 74% SCR Day 0Day 42Day 0Day 42 All lotsPlacebo ≥ 65 N= % SCR Day 0Day 42Day 0Day 42 All lotsPlacebo Day 42 Lot ALot BLot C GMT (95% CI) Langley et al. JID 2011; 203:

28 A-28 Pivotal Trial Data Fulfill Immunogenicity Requirements for Accelerated Approval Q-Pan H5N1 given 21 days apart met CBER criteria in adults and ≥ 65 years of age Manufacturing consistency demonstrated 3.75 µg HA + AS03 A formulation had better immunogenicity profile than currently licensed vaccine (not studied concurrently)

29 A-29 Clinical Endpoint Data from Vaccines Manufactured Using Quebec Process

30 A-30 Q-QIV-006: To Confirm the Clinical Benefit of Influenza Vaccine Antigens Manufactured in Quebec (8 Countries in Caribbean and Asia, ) *Only for primed subjects † Only for unprimed Havrix (N = 2,600) Blood sample † Vaccination † Blood sample* Vaccination Blood sample Day 0 Q-QIV (N = 2,600) (unadjuvanted) Age stratified 3 – 4 and 5 – 8 years ILI case count ~OCT Surveillance during influenza season Havrix dose 2* or 3 † for control group N~5,200 Visit Day 180 Blood sample Day 28Day 56 Children 3 to 8 years of age Randomization 1:1

31 A-31 Q-QIV-006 Evaluated Vaccine Efficacy Against Two Influenza Disease Endpoints Any influenza –Temperature ≥ 37.8° C, and –One or more symptoms on the same day (cough, sore throat, runny nose or nasal congestion) Moderate to severe influenza = “any influenza” plus –Fever > 39°C, or –Physician-verified acute otitis media, or –Physician-verified lower respiratory infection, or –Physician-diagnosed serious extra-pulmonary complication of influenza Definitions for Influenza Confirmed by RT-PCR Test for Viral RNA

32 A-32 Q-QIV-006 Confirmed Efficacy of Influenza Vaccine Antigens Manufactured in Quebec ATP Cohort for Efficacy Q-QIV N=2,379 Havrix N=2,398 Vaccine efficacy (95% CI) Endpointn%n%LLUL Any influenza A or B *67.29 Moderate to severe influenza A or B **86.30 * Success criterion, LL >30% ** 97.5% CI, success criterion, LL >0% Post-hoc analysis, TVC Q-QIV N=2,379 Havrix N=2,398 Vaccine efficacy (95% CI) Endpointn%n%LLUL Any influenza H1N Any influenza H3N

33 A-33 Q-Pan H1N1-035 Confirmed the Value of Adding AS03 to Influenza Vaccine Antigens Manufactured in Quebec (8 Countries in Latin America & Asia, TVC=6,145) Q-Pan H1N1 =1.9 µg HA /AS03 B x2 Q-Pan H1N1 = 1.9 µg HA/AS03 B x1 H1N1 control = 7.5 or 15 µg HA x Time (Days) Disease Free Proportion GroupRelative VE (95% CI)Comment Q-Pan H1N1 x2 vs control76.8 (18.5, 93.4) Primary objective Q-Pan H1N1 x1 vs control46.4 (-34.4, 78.6) Secondary objective Children 6 months to 9 years of age followed for 385 days

34 A-34 Q-Pan H1N1 Was Consistently Effective in Canada StudyDesignAge Vaccine Effectiveness (95% CI) New Brunswick 1 Community-based case-control test-negative design 6 months to 9 years 100% (79.5%, 100%) Manitoba 2 Community-based case-control test-negative design 6 months and older 86% (75%, 93%) Canada Multi-Province 3 Community-based sentinel physician system; case-control test-negative design 6 months and older 93% (69%, 98%) 1 Van Buynder et al., Influenza Other Respi Viruses 2010;4(4): Mahmud et al., Vaccine 2011;29(45): Skowronski et al., BMJ 2011;342:c7297

35 A-35 Clinical Trial Data with Influenza Vaccines Manufactured in Quebec Support that Q-Pan H5N1 Will Reduce Risk of Disease Unadjuvanted Q-QIV Adjuvanted Q-Pan H1N1 55% efficacy - “any” influenza 59% efficacy - “any” H1N1 influenza 73% efficacy - “moderate-severe influenza” 77% relative efficacy - “any” H1N1 influenza % effectiveness - “any” H1N1 influenza VE Q-Pan = VE control + (rel eff x [100% - VE control ]) 90% = 59% + (77% x [100% - 59%]) 90% absolute efficacy – “any” H1N1 influenza GSK proposes Q-QIV-006 as the required study to confirm clinical benefit of Q-Pan H5N1 (it provides a minimum estimate)

36 A-36 GSK Will Collaborate in Government-Sponsored Studies of Q-Pan H5N1 Effectiveness in a Pandemic Observational study  feasible and reliable if –Population-based, test-negative controls –Cases systematically evaluated –Vaccination status captured by product In the US and Canada (where Q-Pan H5N1 might be deployed), governments are best able to conduct observational studies –Control vaccine distribution –Guide case assessments (testing for H5N1 disease) –Capture vaccination status

37 A-37 Introduction Donna Boyce Head, North America Global Regulatory Affairs Immunogenicity & Effectiveness Bruce Innis, MD Vice President Vaccine Discovery and Development Safety Felix Arellano, MD Vice President Vaccines Clinical Safety and Pharmacovigilance ConclusionDonna Boyce GSK Presentation

38 A-38 Non-clinical safety data Clinical trial safety data Analysis of signals from H5N1 and H1N1 (Integrated Summary Safety [ISS]-1, ISS-2 and postmarketing) Pharmacovigilance Plan Relative benefit scenarios in a pandemic setting Assessment of safety and benefit-risk Safety Presentation Outline

39 A-39 Non-clinical safety data Clinical trial safety data Analysis of signals from H5N1 and H1N1 Pharmacovigilance Plan Relative benefit scenarios in a pandemic setting Assessment of safety and benefit-risk Safety Presentation Outline

40 A-40 Non-clinical Safety Data Supported Testing in Humans Standard non-clinical toxicology studies (n=12) –Local tolerance, single-dose toxicity, repeat-dose toxicity, genotoxicity, and reproductive and developmental toxicity studies Standard safety pharmacology studies (n=2) –Cardio-respiratory function in rats and dogs Findings –Injection site inflammation as expected with adjuvanted vaccine

41 A-41 Non-clinical safety data Clinical trial safety data: Pivotal trial Q-Pan H5N1-002 Analysis of signals from H5N1 and H1N1 Pharmacovigilance Plan Relative benefit scenarios in a pandemic setting Assessment of safety and benefit-risk Safety Presentation Outline

42 A-42 Clinical Trial Data: Pivotal Study Q-Pan H5N1-002 N = 4,561 subjects –3,422 Q-Pan H5N1 recipients –1,139 placebo recipients Follow-up to 12 months –2,606 Q-Pan H5N1 recipients –870 placebo recipients Solicited local and general symptoms for 7 days after each dose Unsolicited AEs through day 84 Medically-attended AEs and SAEs through day 364

43 A-43 Q-Pan H5N1-002: Increased Incidence of Local Reactogenicity Compared to Placebo Q-Pan H5N1 Placebo

44 A-44 Q-Pan H5N1-002: Increased Incidence of General Reactogenicity, But Not Grade 3 Events, Compared to Placebo Q-Pan H5N1 Placebo

45 A-45 Q-Pan H5N1-002: Conclusions Greater frequency and intensity of reactogenicity for Q-Pan H5N1 compared to saline placebo Similar frequencies between Q-Pan H5N1 and placebo for –Lymphadenopathy –Unsolicited adverse events –MAEs –SAEs, including fatal AEs –AEs leading to withdrawal

46 A-46 Non-clinical safety data Clinical trial safety data Analysis of signals from H5N1 and H1N1 (ISS-1, ISS-2 and postmarketing) Pharmacovigilance Plan Relative benefit scenarios in a pandemic setting Assessment of safety and benefit-risk Safety Presentation Outline

47 A-47 Main Safety Signals 1 Related to the GSK Adjuvanted Pandemic Influenza Program SignalSourceAssessment Potential Immune- Mediated Diseases Numerical imbalance in ISS-1 Current data do not support causal association Narcolepsy D-Pan H1N1 postmarketing Inconclusive; additional studies ongoing Autoimmune Hepatitis Q-Pan and D-Pan H5N1 clinical development Current data do not support causal association Anaphylaxis Q-Pan H1N1 postmarketing Similar to other flu vaccines Guillain-Barré Syndrome Pre-specified Excess risk 0-2 / million persons vaccinated Solid Organ Transplant Rejection Q-Pan H1N1 postmarketing Current data do not support causal association; additional studies ongoing 1 CIOMS IV/VI definition: report(s) of an event with an unknown causal relationship to treatment that is recognized as worthy of further exploration and continuous surveillanc e

48 A-48 pIMDs: H5N1 Signal Evaluation Included Data from H1N1 Pandemic Response Source of signal: group of AEs that, together, occurred more frequently among H5N1 recipients than control recipients Evaluation of signal –Creation of case series (qualitative analysis; medical review) –Examination of H1N1 clinical trial data –External analysis of H1N1 vaccines’ spontaneous reports (EudraVigilance) –External analysis of H1N1 vaccines (Swedish study)

49 A-49 Aggregate Data from H5N1 and H1N1 Adjuvanted Pandemic Clinical Development Programs Aggregate data analyses = Integrated Summaries of Safety (ISSs) ISS-1 –9,873 D-Pan and Q-Pan H5N1 recipients (8 trials) –Numerical imbalance for pIMDs in aggregate pIMDs identified by 120 MedDRA Preferred Terms List of terms developed with input from external experts and CBER ISS-2 –11,376 D-Pan and Q-Pan H5N1 recipients –28 adult clinical trials of Q-Pan and D-Pan H5N1 and H1N1 vaccines Included all trials in ISS-1 –Numerical imbalance for pIMDs persisted

50 A-50 pIMDs Reported by H5N1 Recipients in Controlled, Uncontrolled and Booster Studies Autoimmune hepatitis (n = 1) Autoimmune thyroiditis or Basedow’s disease (n = 2) Celiac disease (n = 1) Crohn’s disease (n = 1) Erythema nodosum (n = 1) IIIrd nerve paralysis (n = 1) IVth nerve paresis (n = 1) Multiple sclerosis (n = 1) Neuritis (n = 1) Optic neuritis (n = 1) Polymyalgia rheumatica (PMR) or temporal arteritis (n = 4) Psoriasis (n = 3) Radiculitis or radiculopathy (n = 1) Rheumatoid arthritis (n = 1) Scleroderma (n = 1) Systemic lupus erythematosus (n = 1) Uveitis (n = 1) Ulcerative colitis (n = 1) VIIth nerve paralysis, facial paresis, or facial palsy (n = 5)

51 A-51 pIMDs: H5N1 Case Review Suggested Pre-existing or Alternative Plausible Causes 3 events accounted for much of the imbalance: Bell’s palsy/facial palsy / facial paresis / VII nerve paralysis (n=5) –One diagnosis subsequently changed to stroke –One event began 8 hours after vaccination and had negative rechallenge (recovered after receiving second dose) Psoriasis (n=3) –One subject had psoriasis at study enrollment and the investigator did not think it had worsened after receiving vaccination –One subject developed guttate psoriasis attributed to a streptococcal infection by the investigator Polymyalgia rheumatica / temporal arteritis (n=4) –One subject had symptoms prior to vaccination; PMR symptomatology did not change; temporal arteritis diagnosed after vaccination –Another diagnosis was changed to fibromyalgia

52 A-52 No Difference in the Reporting of Autoimmune Diseases Between Adjuvanted and Non-adjuvanted H1N1 Vaccines EudraVigilance data and literature review All spontaneous cases reported to EU during pandemic for all H1N1 vaccines (adjuvanted and non-adjuvanted) Reporting rates of autoimmune diseases, per million –Adjuvanted 6.87 (95% CI: 6.06–7.68) –Non-adjuvanted 9.98 (95% CI: 6.81–13.16) Isai et al., Vaccine 2012; 30:

53 A-53 No Increased Risk of Selected Autoimmune Diseases Among Persons Vaccinated with D-Pan H1N1 Retrospective cohort study in Stockholm county, Sweden; 1.02 million vaccinated; 921 K unvaccinated followed over 8-10 months Bardage et al., BMJ 2011; 343:d5956 EventAdjusted Hazard Ratio95% CI Rheumatoid Arthritis0.94(0.81, 1.09) Insulin-dependent Diabetes 0.99(0.67, 1.47) Inflammatory Bowel Disease 1.13(0.97, 1.32) Multiple Sclerosis0.93(0.68, 1.26) Guillain-Barré Syndrome 1.07(0.66, 1.74) Bell’s Palsy1.25(1.06, 1.48)

54 A-54 pIMDs – Conclusion Currently available data from clinical trials, spontaneous reports and an epidemiological study do not support a relationship between Q-Pan H5N1 and the induction of pIMDs GSK will continue to monitor reports of pIMDs when vaccine is used

55 A-55 Narcolepsy: Context of Signal Evaluation During pandemic –Mass vaccination with GSK H1N1 vaccines in 47 countries –High coverage and/or exclusive use in several countries (Finland, Sweden, Canada) Feb 2010 –First case report received by GSK; reported in sPSUR; monitoring initiated Apr end May 2010 –Second case (April), additional 2 cases Jul-Aug 2010 –Sweden reports cluster of cases –GSK first analysis and EMA mandates investigation –Widespread media attention begins in EU

56 A-56 Narcolepsy: Background Narcolepsy: Background Very rare disease –Background incidence around 10 per million person-years –Incidence lower in children 1-5 per million person-years 1 Difficult to diagnose / validate –Characterized by excessive daytime sleepiness and sleep paralysis 2, frequently associated with cataplexy 3 –Diagnosis requires access to sleep clinic –Decreased hypocretin-1 in CSF 4 HLA DQB1*0602 allele – necessary –Present in 15-25% of population, more prevalent in N. Europe –Possible autoimmune mechanism 1 VAESCO report Han et al. Respirology 2012; doi: /j x 3 Dauvilliers et al : Lancet 2007; 369: 499–511 4 Mignot, et al.. Arch Neurol 2002; 59: 1553–1562

57 A-57 Narcolepsy: Summary of Exposure Clinical trials –almost 23,000 subjects in H5N1 and H1N1, no reports Q-Pan H1N1: 58.5 million vaccinated –111,836 pregnant women; 2.8 million children D-Pan H1N1: 31 million vaccinated –194,780 pregnant women; 6.7 million children

58 A-58 Narcolepsy: Q-Pan H1N1 - No Evidence of a Signal from Epidemiological Study Narcolepsy: Q-Pan H1N1 - No Evidence of a Signal from Epidemiological Study Quebec study (preliminary results) Total 20 cases (6 exposed cases and 14 non-exposed cases) Incidence rate 0.13 per 100,000 person-years (vaccinated and unvaccinated) Age- and gender-adjusted risk ratio 1.06 (95% CI: 0.33, 2.97) J. Montplaisir, Université de Montréal, personal communication

59 A-59 Summary of Results from European Epidemiological Studies StudyCountryRR (95%CI) Attributable Risk (per 100,000) VAESCO (EU) Finland10.2 (1.8-Inf) Not calculated Sweden3.5 (0.4-Inf) Signalling countries pooled (SWE, FIN) 14.2 (2.5-Inf) Non-signalling countries 1.6 ( ) THL (Finland)Finland12.7 ( )6.25 MPA (Sweden)Sweden6.6 ( )3.6 Irish Dept. of Health Ireland13.0 (4.8–34.7)5.3 ANSM/AFFSAPS (France) France < 19 years 5.1 (2.1 – 12.3) ≥ 19 years 3.9 (1.4 – 11) Not calculated

60 A-60 D-Pan H1N1: VAESCO Study - Primary Analysis Yields Inconclusive Results Commissioned by European CDC, robust, large-scale, standardised case-control study, attempting to consider biases Signaling countries (where signal arose; predefined): association in children Non-signaling countries: no association in children *95% CI: 1.8-  Non-signaling countriesSignaling countries Relative Risk Pooled NorwayFranceDenmarkNLUKSwedenFinland * 14.2*

61 A-61 D-Pan H1N1: Main Limitations of Studies Close temporal proximity between H1N1 peak and vaccination – potentially confounds results Important potential referral and ascertainment / recall biases not fully accounted for in most studies to date –Biases better accounted for by VAESCO study Lack of adjustment for potential confounders, such as co-morbidities Swedish study included spontaneous reports as cases, biasing results towards association with vaccine

62 A-62 GSK’s Ongoing Narcolepsy Research Activities Non-clinical and epidemiological investigations ongoing –Epidemiologic study (Quebec) –Non-clinical experiments –Animal studies Research plan developed after experts consultation Agreed by Regulatory Authority (EMA Scientific Advice) Conducted in collaboration with recognized experts

63 A-63 Narcolepsy: Summary No signal to date with Q-Pan H5N1 No signal to date with Q-Pan H1N1 Signal with D-Pan H1N1 D-Pan H1N1 in EU: observational data – inconclusive –Currently available data insufficient to determine whether there is a causal relationship between D-Pan H1N1 and narcolepsy and further research is necessary Extensive research program under way

64 A-64 Non-clinical safety data Clinical trial safety data Analysis of signals from H5N1 and H1N1 Pharmacovigilance Plan Relative benefit scenarios in a pandemic setting Assessment of safety and benefit-risk Safety Presentation Outline

65 A-65 Q-Pan H5N1: Pharmacovigilance Plan (PVP) Includes general (e.g., all pandemic flu vaccines) and specific (e.g., Q-Pan H5N1) activities Specific activities depend upon circumstances of use for vaccine (e.g., civilian or military population)

66 A-66 Q-Pan H5N1: Pharmacovigilance Plan for US Activities to be agreed-upon with CBER: Close monitoring of “adverse events of special interest” (AESIs) for all pandemic vaccines 1, plus autoimmune hepatitis, increased concentrations of hepatic enzymes, narcolepsy Weekly, computerized signal detection 2 Monthly simplified Periodic Safety Update Reports to regulators 2 Will rely on US agencies for near real-time analysis of AEs in data systems not available to sponsors –Rapid-cycle analysis of VSD –Mini-sentinel or Sentinel 1 Anaphylaxis, Bell’s palsy, convulsions, demyelinating disorders, encephalitis, Guillain-Barré syndrome neuritis, vasculitis, vaccination failure 2 During H5N1 pandemic

67 A-67 Q-Pan H5N1: Pharmacovigilance Plan for US The following activities will be contingent on their feasibility at the time of vaccine use: Establish US Pregnancy Registry, as is done for seasonal flu vaccines Determine background incidence rates in US for AESIs and other AEFIs, as necessary, for observed:expected analyses Conduct prospective cohort study Continue to work with sleep experts and professional societies to establish sentinel network for early detection and validation of narcolepsy cases

68 A-68 Non-clinical safety data Clinical trial safety data Analysis of signals from H5N1 and H1N1 Pharmacovigilance Plan Relative benefit scenarios in a pandemic setting Assessment of safety and benefit-risk Safety Presentation Outline

69 A-69 Potential Impact of an H5N1 Pandemic Current status of H5N1 human disease (2003 – 2012) –608 cases with 359 deaths reported to WHO –Overall case fatality ratio 59%* Projected social consequences of H5N1 pandemic –US: 25-50% of population infected; 1-5% mortality, 2 million excess deaths –Worldwide: 25-50% morbidity; 16 million – 160 million excess deaths *http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/index.html

70 A-70 Relative Benefit of H5N1 Vaccines on Mortality: Exploratory Model Assumptions ParameterAgeLowMidHighSource Vaccine Effectiveness Q-Pan H5N1 Adult D-Pan H1N1 effectiveness studies Vaccine Effectiveness Non-adjuvanted Adult Inferred from immunogenicity* Attack RateAny Past pandemics (1918, 1957, 1968) Case Fatality RatioAny *Treanor, et al., N Engl J Med 2006; 354:

71 A-71 Relative Benefit Scenarios in a Pandemic Setting (Conservative Analysis) Scenarios VE Q-Pan H5N1 VE Non- Adjuvanted AR Case Fatality Ratio Prevented Deaths Adjuvanted * Prevented Deaths Non- Adjuvanted* Best Most Realistic Worst *per 100,000 persons vaccinated. VE = vaccine effectiveness, AR = attack rate,

72 A-72 Relative Benefit: Adjuvanted Vaccine Prevents Approximately Twice as Many Deaths as Non-Adjuvanted Vaccine in All Scenarios Prevented deaths per 100,000 persons vaccinated Best case

73 A-73 Non-clinical safety data Clinical trial safety data Analysis of signals from H5N1 and H1N1 Pharmacovigilance Plan Relative benefit scenarios in a pandemic setting Assessment of safety and benefit-risk Safety Presentation Outline

74 A-74 Overall Safety and Benefit-Risk Conclusions Q-Pan H5N1 safety profile supports licensure for the proposed indication Reactogenicity (general and local) is greater than for placebo Benefit-risk balance of Q-Pan H5N1 is positive Pharmacovigilance Plan is built upon experience with H1N1 pandemic and will allow GSK to monitor the safety of Q-Pan H5N1

75 A-75 Introduction Donna Boyce Head, North America Global Regulatory Affairs Immunogenicity & Effectiveness Bruce Innis, MD Vice President Vaccine Discovery and Development Safety Felix Arellano, MD Vice President Vaccines Clinical Safety and Pharmacovigilance ConclusionDonna Boyce GSK Presentation

76 A-76 Pathway for Accelerated Approval of Q-Pan H5N1 US Licensed Seasonal Influenza Vaccine Accelerated Approval Efficacy not yet confirmed Source FluLaval Pre-approval BLA 2013 During a Pandemic Timing Q-Pan H5N1 licensure approach: Accelerated Approval Safety Immunogenicity Q-Pan H5N1-001 Q-Pan H5N1-002 Effectiveness of Q-Pan H5N1 inferred when the efficacy of the seasonal confirmed FluLaval Q-QIV-006 Post-approval Work with US Gov’t to collect safety/effectiveness data with Q-Pan H5N1 CBER Guidance

77 A-77 Benefit-Risk is Positive Q-Pan H5N1 immunogenicity and safety profile support licensure for the proposed indication AS03 –High immunogenicity –Antigen-sparing Global H1N1 pandemic experience will enable effective safety monitoring of Q-Pan H5N1 through planned pharmacovigilance

78 A-78 Licensure Improves Pandemic Preparedness Offers US Government more immunogenic alternative to currently licensed H5N1 vaccine Establishes regulatory platform to enable rapid licensure of pandemic strain specific vaccine Antigen-sparing property will increase number of doses available for distribution Significant public health benefit in event of H5N1 pandemic

79 A-79 Additional as Slides Shown

80 D-Pan H5N1 Heterologous Protective Efficacy in Ferrets < (15-83) 43 (16-116) 35 (12-107) 26 (12-55) A/Indonesia Neut GMT (95% CI) Groups of 6 animals challenged with TCID 50 A/Indonesia5/05 IT after immunization with 2 doses of A/Vietnam antigen with or w/o adjuvant Baras, 2008 PLoS One 3(1);e1401 E-2

81 Clinical Trial Experience with Q-Pan and D-Pan BLA focuses on 2 pivotal (N = 5,341) and 4 supportive (N = 1,153) Q-Pan H5N1 studies and 2 integrated summaries of safety for adults (N = 22,521) Number of studies Total Vaccinated Cohort Received AS03-adjuvanted Pandemic Flu Vaccine H5N1 Studies (D-Pan and Q-Pan) Adults1814,66812,058 Children61,8761,436 H5N1 Total2416,54413,494 H1N1 Studies (D-Pan and Q-Pan) Adults168,1734,972 Children127,9665,428 H1N1 Total2816,13910,400 Grand Total 5232,68323,894 E-3

82 Q-Pan H5N1-001 Heterologous H5N1 MN Data (A/Indonesia/05/2005 vaccine at Day 0 and Day 42) A/Indonesia (clade 2.1)GMT>1:28VRR Group Time point N VALUE 95% CI % % LLULLLULLLUL Q 3.8 µg + AS03 A PRE D A/Vietnam (clade 1) Q 3.8 µg + AS03 A PRE D A/Anhui/1/05 (clade 2.3) Q 3.8 µg + AS03 A PRE D A/Turkey/1/05 (clade 2.2) Q 3.8 µg + AS03 A PRE D VRR = vaccine response rate = 4-fold or great increase in MN titer Plain antigen A/Indo 3.75µg HA A/Indo  GMT: PRE: 25.7; Day 42: 183.8; VRR: 73.5% A/Vietnam GMT: PRE: 55.7; Day 42: 143.9; VRR: 30.6 (no data A/Anui or A/turkey) E-7

83 PlaceboQ-Pan 18-64≥65≥75 D0D42D182D0D42D182D0D42D182D0D42D182D0D42D182D0D42D182 Q-Pan-002: HI Immunogenicity to Day 182 (GMTs and SCRs) 4,561 adults vaccinated twice with 3.75µg + AS03 A or Saline Placebo Langley et al., JID 2011; 203: E-13

84 Q-Pan H5N1-005 Heterologous Prime-Boost Subjects ≥18 years of age. ~120 per 7 groups (N=841) A/Indonesia prime (Clade 2.1) with A/turkey boost (Clade 2.2) 6 or 18 months later CBER immunogencity criteria were met 10-days following booster vaccination, but booster responses were less in those primed with unadjuvanted vaccine HI GMTs for A/turkey/Turkey/05/2005 DoseInterval 3.75+AS03 B M0+M AS03 B M0+M AS03 A M0+M AS03 B M0+M AS03 A M0+M AS03 B M0+M AS03 A M6+M18 E-15

85 D-Pan H5N1-007 Frequency of CD4 T-Cells Specific for H5N1 A/Vietnam Split Antigen ***: p<0.001: significancy for adjuvant effect Moris P, et al., J. Clin. Immunol. 2011;31(3): E-18

86 Q-Pan H5N1-009: Rapid Dosing Adults years of age receiving two doses of 3.75 µg + AS03 A 78 subjects per group (N=312) D0 + D21 D0 + D14 D0 + D7 D0 + D PRED7D14D21D28D35D42 Day GMT 97% SCR 93% SCR 72% SCR Lasko et al., JID 2011; 204: HI GMT – Vaccine Homologous (A/Indonesia/5/2005) E-21

87 Q-Pan H5N1-010 Boost of Q-Pan-001 Subjects (value of adjuvanted vaccine priming and boosting) Q-Pan H5N1-001 Veterans received heterologous (A/turkey) boost 15 months later Q-Pan and D-Pan A/turkey HI responses equivalent (pooled in figure below) GMT and SCR 10-days following booster vaccination shown below Q-Pan H5N1-001 dosing Boost with A/turkey 3.75µg HA + AS03 A Boost with A/turkey 3.75µg HA 92% SCR 96% SCR 97% SCR 68% SCR 70% SCR Q Indo 3.75 x2Q&D Indo AS03 A x2 Q&D Indo AS03 B x2 Q&D Indo AS03 A x2 Q&D Indo AS03 B x2 HI GMT Risi et al., Vaccine 2011; 29: E-23

88 Q-QIV-006 Vaccine Efficacy by Sub-Type/Lineage (Total vaccinated cohort – post hoc exploratory analysis) EventGroup ARVE 95% CI Nn%LLULT/N%LLUL Moderate to severe - Type A Q-QIV HAVRIX Moderate to severe - H1N1 Q-QIV HAVRIX Moderate to severe - H3N2 Q-QIV HAVRIX T/N = mean follow-up period in each group (person-months) Vaccine efficacy assessed using Cox Regression model adjusted for covariates (age category, region, priming status) E-29

89 Q-QIV-006 Immunogenicity Geometric Mean Titer 28 Days After Vaccination (ATP immunogenicity subset) Q-QIVHavrix™ Control E-30

90 Immunogenicity Comparisons Q-Pan H1N1 to H5N1 Different dosing regimens –Q-Pan H1N1: single dose –Q-Pan H5N1: 2 doses, given 21 days apart Similar HI antibody responses are observed in adults Post-Vaccination Log 10 GMT w/ 95% CI Seroconversion Rate w/ 95% CI 65+ E-35

91 Q-Pan H5N1-021: HI Responses SCR:57.5%100%58.5%99.5% 51.5%99.0% E-43

92 Q-Pan H5N1-021: Incidence of Injection Site Pain by Dose Number and Age E-44

93 Q-Pan H5N1-021: Incidence of fever per dose for children <6 years E-45

94 Quebec* and Dresden* Manufacturing Processes Downstream Process & Formulation QuebecDresden virus inactivated UV followed by formaldehyde virus concentrated and purified by zonal centrifugation using a linear sucrose density gradient solution containing detergent to split the virus purified by centrifugation and disrupted by deoxycholate further purified by diafiltration inactivated by consecutive effect of deoxycholeate and formaldehyde Tween-80, triton X-100 and magnesium chloride used as excipients for the formulation * As per US PI 2012/2013 No Difference In Upstream Process MW-1MW-94

95 Injection site pain (18 to 64 years) (Q-Pan-002) S-5

96 Autoimmune Hepatitis: Evidence Does Not Support a Causal Relationship Q-Pan H5N1 and D-Pan H5N1 clinical trials 2 reports –Q-Pan-H5N1 002 – 29 y/o male, AIH experts considered diagnosis doubtful, possibly non-specific reactive hepatitis; likely prevalent disease –D ‑ Pan H5N1 009– 3.5 y/o, female; probable AIH, prevalent (pre-existing) disease Both CHMP and a panel of external experts concluded, after review of GSK’s of H5N1 and H1N1 clinical development programs: the evidence does not support a causal association between AS03-adjuvanted vaccines and AIH S-15

97 Autoimmune Hepatitis: D-Pan H1N1 Spontaneous Reports Postmarketing use of D-Pan H1N1 5 spontaneous reports at least 31 million doses administered well below the expected (background) incidence of 1 – 2 cases/100,000 person-years, taking underreporting into account Abdominal pain, nausea and cold sweat 7 mos prior to vaccination Definite AIH: score  7; Probable AIH: score  6 S-16

98 Non-Adjuvanted H1N1 Vaccine Postmarketing Studies: Guillain-Barré Syndrome (GBS) SCCS= Self controlled case series Author (country) Study design (Age range) N Cases N Exposed Adjuvant OR: overall + age stratified 95% CI Tokars, 2012 (USA) SCCS (1 – 84) 59 Non- adjuvanted Overall: 2.1 (1.2 – 3.5) 0.5 – 24: 3.0 (1.0 – 9.1) 25 – 49: 2.0 (0.7 – 5.5) 50 – 64: 2.1 (0.8 – 5.6) ≥ 65: 1.0 (0.5 – 4.3) Greene, 2012 (USA) Self controlled risk interval (1- 71) 2913 Non- adjuvanted Overall: 4.4 (1.3 – 14.2) Wise, 2012 (USA) Cohort41129 Non- adjuvanted Overall: 1.57 (1.02 – 2.21) < 25: 1.67 (0.58 – 3.22) ≥ 25: 1.54 (0.90 – 2.25) Yih, 2011 (USA) Self controlled risk interval (< ) 53 Non- adjuvantedOverall: 2.5 (0.42 – 15.0) S-34

99 Adjuvanted H1N1 Vaccine Postmarketing Studies: Guillain-Barré Syndrome (GBS) SCCS= Self controlled case series S-35

100 SOTR: Results of selected, published studies Study sizeOutcome Reference 216 SOTR 138 controls No increase in incidence of graft rejection Siegrist kidney TRAnti-HLA antibodies in 17.3% and 11.9% (2 cohorts) vs. 6% in historical controls (seasonal TIV); transient, no change in graft function Katerinis kidney TRNo change in anti-HLA I/II antibody prevalence Broeders heart TRNo clinical graft rejection Meyer heart TR 60 controls No clinical graft rejection, increase in cellular rejection on biopsies (small numbers, limited adjustment for confounding) Schaffer lung TRNo rejection events reported Schuurmans kidney TR5.6% de novo DSA, comparable to seasonal flu vaccine; 2 humoral rejections with graft loss (no unvaccinated controls) Brakemeier heart TRNo clinical evidence of rejection after 6 months follow-up Altamirano liverSimilar % of AEs in vaccinated transplant recipients and healthy controls. No clinical rejection Goldschmidt kidneyNo rejection events reported Crespo 2011 S-39


Download ppt "A-1 Q-Pan H5N1 Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted Donna Boyce Head North America, Global Regulatory Affairs GlaxoSmithKline Vaccines."

Similar presentations


Ads by Google