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

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Q-Pan H5N1Influenza A (H5N1) Virus

Monovalent Vaccine, Adjuvanted

Donna BoyceHead North America, Global Regulatory Affairs

GlaxoSmithKline Vaccines

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Introduction Donna BoyceHead, North AmericaGlobal Regulatory Affairs

Immunogenicity & Effectiveness

Bruce Innis, MDVice PresidentVaccine Discovery and Development

Safety Felix Arellano, MDVice PresidentVaccines Clinical Safety and Pharmacovigilance

Conclusion Donna Boyce

GSK Presentation

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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

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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

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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

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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

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Q-Pan H5N1 Registered in 30 Countries

Q-Pan H5N1 Under Review

Q-Pan H5N1

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GSK’s H1N1 Pandemic Experience: Registered in > 50 Countries Worldwide

Quebec & Dresden H1N1 Registrations

> 90 Million Doses Administered

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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 doseD,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

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Pathway for Accelerated Approval of Q-Pan H5N1

US Licensed Seasonal Influenza Vaccine

Accelerated Approval

Efficacy not yet confirmed

Source

FluLaval

Pre-approval

2006

2012 BLA

2013

During a Pandemic

Timing

Q-Pan H5N1 licensure approach: Accelerated Approval

• Safety• Immunogenicity

Q-Pan H5N1-001Q-Pan H5N1-002

Effectiveness of Q-Pan H5N1 inferred when the efficacy of the seasonal confirmed

FluLavalQ-QIV-006

Post-approval

Work with US Gov’t to collect safety/effectiveness data

with Q-Pan H5N1CBER Guidance

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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 + AS03A) or any formulation with AS03 for ISS

Supportive H1N1

EffectivenessStudies

Pivotal StudiesN=5,341 (3,574)

Supportive Dosing Interval and

Booster StudiesN=1,153 (431)

Dose FindingStudy

N=400 (0)

Q-Pan-009Short Interval

18-64 years

Q-Pan-005Long Interval

≥ 18 years

Q-Pan-010Boost 00118-64 years

D-PanH5N1-00718-64 years

Q-Pan-001Dose

Confirmation18-64 years

Q-Pan-002Safety,

Consistency≥ 18 years

New Brunswick6 mo-9 years

Manitoba≥ 6 months

CanadaMulti-Province

≥ 6 months

SupportiveSafety

SummariesN=22,521 (16,160)

H5N1ISS-1 [2009]

≥ 18 years

H5N1+H1N1ISS-2 [2011]

≥ 18 years

BLA Database

Q-QIV-006Absolute Vaccine Efficacy

3-8 years

Q-Pan H1N1-035Relative Vaccine Efficacy

6 mo-8 years

Post-Licensure Commitment Key Supportive Data

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GSK Presentation

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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 process

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CBER Immunogenicity Criteria

CBER’s Immune ResponseThresholds

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

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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, 18-20 October 2006, Vienna, AustriaGarçon et al., Expert Rev. Vaccines 2012; 11(3), 349–366

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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; 29:2461-2473

Characterized in vivo in mice, ex vivo in human cells

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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 + AS03A) or any formulation with AS03 for ISS

Supportive H1N1

EffectivenessStudies

Pivotal StudiesN=5,341 (3,574)

Supportive Dosing Interval and

Booster StudiesN=1,153 (431)

Dose FindingStudy

N=400 (0)

Q-Pan-009Short Interval

18-64 years

Q-Pan-005Long Interval

≥ 18 years

Q-Pan-010Boost 00118-64 years


Q-Pan-001Dose


Q-Pan-002Safety,





≥ 6 months

SupportiveSafety

SummariesN=22,521 (16,160)

H5N1ISS-1 [2009]

≥ 18 years

H5N1+H1N1ISS-2 [2011]

≥ 18 years

BLA Database

Q-QIV-006Absolute Vaccine Efficacy

3-8 years

Q-Pan H1N1-035Relative Vaccine Efficacy

6 mo-8 years

Post-Licensure Commitment Key Supportive Data


Q-Pan-001Dose


Q-Pan-002Safety,





≥ 6 months

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Q-Pan H5N1 Immunogenicity Data

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SC

R (

%)

0

25

50

75

100

Post dose 1 Post dose 2

3.75µg7.5µg 15µg 30µg

3.75µg + AS03A

7.5µg + AS03A

15µg + AS03A

30µg + AS03A

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

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Q-Pan H5N1-001: To Confirm AS03 Benefit, Equivalence to D-Pan, and AS03 Dose

(Total Vaccinated Cohort = 780 adults, USA/Canada, 2007-8)

Q-Pan 3.75 µg N=78

Q-Pan 3.75 µg + AS03A N=152

Q-Pan 3.75 µg + AS03B N=150

D-Pan 3.75 µg + AS03A N=151

D-Pan 3.75 µg + AS03B N=149

Q-Pan 1.9 µg + AS03A N=50

Q-Pan 1.9 µg + AS03B N=50

Adjuvant benefit

Immunogenicityequivalence

If Q-Pan/AS03 groups have SPR ≥ 76%, enrollhalf dose groups

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Q-Pan H5N1-001 Confirmed AS03 Benefit (SCR increase > 15%)

(Per Protocol Immunogenicity Cohort)

0

10

20

30

40

50

60

70

80

90

100

SP

R (%

)

A/Indonesia HI ResponsesGroup Size 140-146 in adjuvant groups, 75 controls

CBER SPR Target

ΔSPR/SCR ~ 80%

Langley et al., JID 2010; 201:1644-53.

Day 0 Day 21 Day 42

Q-Pan Only Q-Pan + AS03A D-Pan + AS03A Q-Pan + AS03B D-Pan + AS03B

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1

10

100

1000

GM

T (9

5%

CI)

A/Indonesia HI Responses,Group size 140-146 in adjuvant groups, 75 controls

Q-Pan H5N1-001 Confirmed AS03 Benefit (GMT increase > 2-fold)


Langley et al., JID 2010; 201:1644-53.

Day 0 Day 21 Day 42

GMT increase 43-fold


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Q-Pan H5N1-001 Confirms Q-Pan Equivalence to D-Pan (GMT ratio within 0.67 – 1.5)


1

10

100

1000

GM

T (9

5%

CI)


GMT ratio 0.94 (95% CI 0.75, 1.17)

Langley et al., JID 2010; 201:1644-53.


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Q-Pan H5N1-001 Shows Good 1-Dose Priming(Per Protocol Immunogenicity Cohort)

1

10

100

1000

GM

T (9

5%

CI)


Anamnestic response requires AS03

Langley et al., JID 2010; 201:1644-53.


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N=80 N=81 N=25 N=26 N = 64 N=65 N=24 N=2420

200

2000

18-40 41-64

Q-Pan H5N1-001 Showed Only 3.75 µg + AS03A Preserved Immunogenicity for Older Adults

(Post hoc analysis)

Langley et al., JID 2010; 201:1644-53

3.75 μg + AS03A 3.75 μg + AS03B 1.9 μg + AS03A 1.9 μg + AS03B

96.3%

98.4%86.2%

96.0%

95.8%92.3%

75.0%

92.6%

GM

T (

95%

CI)

Day 42 Immunogenicity (Homologous HI) as GMT and SPR

GMT and/or SPR decreased

GMT and SPR preserved

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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, 18-49 yrs

Ag lot B + AS03 lot 2 N=568, 18-49 yrs

Ag lot C + AS03 lot 3 N=569, 18-49 yrs

Placebo (PBS) N=568, 18-49 yrs

Ag lot ABC + AS03 lot 1 N= 597, 50-64 yrs

Placebo (PBS) N=200, 50-64 yrs

Ag lot ABC + AS03 lot 1 N=1118, > 64 yrs

Placebo (PBS) N=371, > 64 yrs

Immunogenicity:SCR & SPRages 18-64

Lot to lot consistency:

GMT ratioages 18-49

Healthy

Stable health

Immunogenicity:SCR & SPRages > 64

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Q-Pan H5N1-002 Demonstrated Good Immunogenicity Regardless of Age


Immunogenicity (Homologous HI) as Day 0 and 42 GMTs and SCRs

Day 0 Day 42 Day 0 Day 42

All lots Placebo

≥ 75

N=11972% SCR

N=39674% SCR


All lots Placebo

≥ 65

N=157191% SCR


All lots Placebo

18-64

1

10

100

1000

Day 42 Day 42 Day 42

Lot A Lot B Lot C

18-49

GM

T (

95%

CI)

Langley et al. JID 2011; 203:1729-38.

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Pivotal Trial Data Fulfill Immunogenicity Requirements for Accelerated Approval

• Q-Pan H5N1 given 21 days apart met CBER criteria in adults 18-64 and ≥ 65 years of age

• Manufacturing consistency demonstrated

• 3.75 µg HA + AS03A formulation had better immunogenicity profile than currently licensed vaccine (not studied concurrently)

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Clinical Endpoint Data from Vaccines Manufactured Using

Quebec Process

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Q-QIV-006: To Confirm the Clinical Benefit of Influenza Vaccine Antigens Manufactured in Quebec

(8 Countries in Caribbean and Asia, 2010-11)

*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 2010-11 influenza season

Havrix dose 2* or 3† for

control group

N~5,200

Visit Day 180

Blood sample

Day 28 Day 56

Children 3 to 8 years of age

Randomization 1:1

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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

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Q-QIV-006 Confirmed Efficacy of Influenza Vaccine Antigens Manufactured in Quebec

ATP Cohort for Efficacy Q-QIVN=2,379

HavrixN=2,398 Vaccine efficacy (95% CI)

Endpoint n % n % % LL UL

Any influenza A or B 58 2.44 128 5.34 55.4 39.15* 67.29

Moderate to severe influenza A or B 14 0.59 52 2.17 73.1 47.11** 86.30

* Success criterion, LL >30%** 97.5% CI, success criterion, LL >0%

Post-hoc analysis, TVCQ-QIV

N=2,379Havrix

N=2,398 Vaccine efficacy (95% CI)

Endpoint n % n % % LL UL

Any influenza H1N1 17 0.66 41 1.59 59.0 27.80 76.69

Any influenza H3N2 20 0.77 50 1.93 60.7 34.00 76.61

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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 /AS03B x2

Q-Pan H1N1 = 1.9 µg HA/AS03B x1

H1N1 control = 7.5 or 15 µg HA x2

100 200 300 400 500 600

Time (Days)

00.985

0.990

0.995

1.000

Dis

ease

Fre

e P

rop

ort

ion

Group Relative VE (95% CI) Comment

Q-Pan H1N1 x2 vs control 76.8 (18.5, 93.4) Primary objective

Q-Pan H1N1 x1 vs control 46.4 (-34.4, 78.6) Secondary objective

Children 6 months to 9 years of age followed for 385 days

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Q-Pan H1N1 Was Consistently Effective in Canada

Study Design AgeVaccine

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):171-82 Mahmud et al., Vaccine 2011;29(45):7975-813 Skowronski et al., BMJ 2011;342:c7297

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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” influenza59% efficacy - “any” H1N1 influenza73% efficacy - “moderate-severe influenza”

77% relative efficacy - “any” H1N1 influenza

86-100% effectiveness - “any” H1N1 influenza

VEQ-Pan = VEcontrol + (rel eff x [100% - VEcontrol]) 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)

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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

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GSK Presentation

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• 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

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• Analysis of signals from H5N1 and H1N1





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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

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• Clinical trial safety data: Pivotal trial Q-Pan H5N1-002






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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

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

0

10

20

30

40

50

60

70

80

90

100

All Grade 3 All > 100 All > 100

Pain Redness (mm) Swelling (mm)

Incidence of solicited local adverse events

Q-Pan H5N1Placebo

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Q-Pan H5N1-002: Increased Incidence of General Reactogenicity, But Not Grade 3 Events,

Compared to Placebo

0

10

20

30

40

50

60

70

80

90

100

All

Gra

de

3 All

Gra

de

3 All

≥39

.0 All

Gra

de

3 All

Gra

de

3 All

Gra

de

3 All

Gra

de

3

Arthralgia Fatigue Fever (°C) Headache Myalgia Shivering Sweating

Incidence of solicited general adverse events

Q-Pan H5N1Placebo

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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

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• Analysis of signals from H5N1 and H1N1 (ISS-1, ISS-2 and postmarketing)





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Main Safety Signals1 Related to the GSK Adjuvanted Pandemic Influenza Program

Signal Source Assessment

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-BarréSyndrome 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 surveillance

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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)

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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

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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)

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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

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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 2009-2010 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: 7123-7129

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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

Event Adjusted Hazard Ratio 95% CI

Rheumatoid Arthritis 0.94 (0.81, 1.09)

Insulin-dependent Diabetes 0.99 (0.67, 1.47)

Inflammatory Bowel Disease 1.13 (0.97, 1.32)

Multiple Sclerosis 0.93 (0.68, 1.26)

Guillain-Barré Syndrome 1.07 (0.66, 1.74)

Bell’s Palsy 1.25 (1.06, 1.48)

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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

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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 2010 - 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

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Narcolepsy: Background

• Very rare disease– Background incidence around 10 per million person-years– Incidence lower in children 1-5 per million person-years1

• Difficult to diagnose / validate – Characterized by excessive daytime sleepiness and sleep

paralysis2, frequently associated with cataplexy3

– Diagnosis requires access to sleep clinic– Decreased hypocretin-1 in CSF4

• HLA DQB1*0602 allele – necessary – Present in 15-25% of population, more prevalent in N. Europe– Possible autoimmune mechanism

1 VAESCO report 20122 Han et al. Respirology 2012; doi:10.1111/j.1440-1843.2012.02178.x 3 Dauvilliers et al : Lancet 2007; 369: 499–5114 Mignot, et al.. Arch Neurol 2002; 59: 1553–1562

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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

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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

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Summary of Results from European Epidemiological Studies

Study Country RR (95%CI) Attributable Risk (per 100,000)

VAESCO (EU)

Finland 10.2 (1.8-Inf)

Not calculated

Sweden 3.5 (0.4-Inf)

Signalling countries pooled (SWE, FIN) 14.2 (2.5-Inf)

Non-signalling countries 1.6 (0.5-6.1)

THL (Finland) Finland 12.7 (6.1-30.8) 6.25

MPA (Sweden) Sweden 6.6 (3.1-14.5) 3.6

Irish Dept. of Health Ireland 13.0 (4.8–34.7) 5.3

ANSM/AFFSAPS (France) France

< 19 years5.1 (2.1 – 12.3)

≥ 19 years3.9 (1.4 – 11)

Not calculated

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 countries Signaling countries

Rel

ati

ve

Ris

k

Pooled PooledNorway France Denmark NL UK Sweden Finland

100

10

1

0.1

2.9

1.3

4.1

1.6

3.5

10.2*14.2*

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

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

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

A-64








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)

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 vaccines1, plus autoimmune hepatitis, increased concentrations of hepatic enzymes, narcolepsy

• Weekly, computerized signal detection2

• Monthly simplified Periodic Safety Update Reports to regulators2

• 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

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

A-68








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

http://www.who.int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/index.html

A-70

Relative Benefit of H5N1 Vaccines on Mortality: Exploratory Model Assumptions

Parameter Age Low Mid High Source

Vaccine Effectiveness Q-Pan H5N1 Adult 0.62 0.67 0.97 D-Pan H1N1

effectiveness studies

Vaccine Effectiveness Non-adjuvanted Adult 0.30 0.44 0.57 Inferred from

immunogenicity*

Attack Rate Any 0.15 0.25 0.40Past pandemics(1918, 1957, 1968)

Case Fatality Ratio Any 0.01 0.02 0.05

*Treanor, et al., N Engl J Med 2006; 354: 1343-1351

A-71

Relative Benefit Scenarios in a Pandemic Setting (Conservative Analysis)

ScenariosVE

Q-Pan H5N1

VE Non- Adjuvanted AR

Case Fatality Ratio

Prevented Deaths

Adjuvanted *

Prevented Deaths Non- Adjuvanted*

Best 0.97 0.57 0.15 0.01 146 86

Most Realistic 0.67 0.3 0.25 0.05 838 375

Worst 0.62 0.3 0.40 0.05 1240 600

*per 100,000 persons vaccinated. VE = vaccine effectiveness, AR = attack rate,

A-72

Relative Benefit: Adjuvanted Vaccine Prevents Approximately Twice as Many Deaths as Non-Adjuvanted Vaccine in All Scenarios

0 200 400 600 800 1000 1200 1400

Prevented Deaths Non Adjuvanted

Prevented Deaths Adjuvanted

Worst case

Most likelycase

Prevented deaths per 100,000 persons vaccinated

Best case

A-73








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

A-75






GSK Presentation

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

2006

2012 BLA

2013

During a Pandemic

Timing

Q-Pan H5N1 licensure approach: Accelerated Approval

• Safety• Immunogenicity

Q-Pan H5N1-001Q-Pan H5N1-002

Effectiveness of Q-Pan H5N1 inferred when the efficacy of the seasonal confirmed

FluLavalQ-QIV-006

Post-approval

Work with US Gov’t to collect safety/effectiveness data

with Q-Pan H5N1CBER Guidance

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

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

A-79

Additional as Slides Shown

D-Pan H5N1 Heterologous Protective Efficacyin Ferrets

0

1

2

3

4

5

6

7

8

0

10

20

30

40

50

60

70

80

90

100

15 ug HA AS03A 1.7 ug HA+AS03A

3.8 ug HA+AS03A

7.5 ug HA+AS03A

15 ug HA+AS03A

Lo

g 1

0 l

un

g v

ira

l lo

ad

(T

CID

50

pe

r g

)

% o

f A

nim

als

fo

un

d d

ea

d /

m

ori

bu

nd

sa

cri

fic

e

< 28 < 28 36

(15-83)

43

(16-116)

35

(12-107)

26

(12-55)

A/Indonesia Neut GMT

(95% CI)

Groups of 6 animals challenged with 105.5 TCID50 A/Indonesia5/05 ITafter immunization with 2 doses of A/Vietnam antigen with or w/o adjuvant

Baras, 2008

PLoS One 3(1);e1401 E-2

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)

Adults 18 14,668 12,058

Children 6 1,876 1,436

H5N1 Total 24 16,544 13,494

H1N1 Studies (D-Pan and Q-Pan)

Adults 16 8,173 4,972

Children 12 7,966 5,428

H1N1 Total 28 16,139 10,400

Grand Total 52 32,683 23,894

E-3

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 >1:28 VRR

GroupTime point

N VALUE95% CI

%95% CI

%95% CI

LL UL LL UL LL UL

Q 3.8 µg + AS03A

PRE 47 22.3 17.4 266.1 27.7 15.6 42.6 - - -

D42 47 1566.8 1227.3 2000.2 100 92.5 100 97.9 88.7 99.9

A/Vietnam (clade 1)

Q 3.8 µg + AS03A

PRE 47 57 41.3 78.6 70.2 55.1 82.7 - - -

D42 47 264.8 216.7 323.6 100 92.5 100 53.2 38.1 67.9

A/Anhui/1/05 (clade 2.3)

Q 3.8 µg + AS03A

PRE 143 14 14 14 0 0 2.5 - - -

D42 142 91.3 78.4 106.4 95.1 90.1 98 78.9 71.2 85.3

A/Turkey/1/05 (clade 2.2)

Q 3.8 µg + AS03A

PRE 143 25.6 21.9 29.9 35.7 27.8 44.1 - - -

D42 143 594.4 523.6 674.7 100 97.5 100 88.8 82.5 93.5

VRR = vaccine response rate = 4-fold or great increase in MN titerPlain 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

1

10

100

1000

GM

T

91% SCR

62% SCR

74% SCR

65% SCR73% SCR

72% SCR

PlaceboQ-Pan

18-64 ≥65 ≥75

D0 D42 D182 D0 D42 D182 D0 D42 D182 D0 D42 D182 D0 D42 D182 D0 D42 D182

Q-Pan-002: HI Immunogenicity to Day 182(GMTs and SCRs)

4,561 adults vaccinated twice with 3.75µg + AS03A or Saline Placebo

Langley et al., JID 2011; 203:1729-38 E-13

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

Dose Interval

3.75+AS03B M0+M6

7.50+AS03B M0+M6

3.75+AS03A M0+M18

3.75+AS03B M0+M18

7.50+AS03A M0+M18

7.50+AS03B M0+M18

3.75+AS03A M6+M18

E-15

D-Pan H5N1-007 Frequency of CD4 T-Cells Specific for H5N1 A/Vietnam Split Antigen

0

500

1000

1500

2000

2500

3000

3500

40003.

8 µg

7.5

µg

3.8

µg +

Ad

j

7.5

µg +

Ad

j

3.8

µg

7.5

µg

3.8

µg +

Ad

j

7.5

µg +

Ad

j

3.8

µg

7.5

µg

3.8

µg +

Ad

j

7.5

µg +

Ad

j

3.8

µg

7.5

µg

3.8

µg +

Ad

j

7.5

µg +

Ad

j

3.8

µg

7.5

µg

3.8

µg +

Ad

j

7.5

µg +

Ad

j

ALL DOUBLES CD4OL IFNg IL2 TNFa

Med

ian

at D

ay42

-Day

0 (Q

1 an

d Q

3)

***

***

***

*** ******

***

***

***: p<0.001: significancy for adjuvant effect

Moris P, et al., J. Clin. Immunol. 2011;31(3):443-54 E-18

Q-Pan H5N1-009: Rapid Dosing

• Adults 18-64 years of age receiving two doses of 3.75 µg + AS03A

• 78 subjects per group (N=312)

D0 + D21

D0 + D14

D0 + D7

D0 + D0

0

100

200

300

400

500

600

700

PRE D7 D14 D21 D28 D35 D42

Day

GM

T

97% SCR

93% SCR

72% SCR

Lasko et al., JID 2011; 204:574-81.

HI GMT – Vaccine Homologous (A/Indonesia/5/2005)

E-21

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

10

100

1000

Q-Pan H5N1-001 dosing

Boost with A/turkey 3.75µg HA + AS03A Boost with A/turkey 3.75µg HA

92% SCR

96% SCR97% SCR

68% SCR70% SCR

Q Indo 3.75 x2 Q&D Indo 3.75+ AS03A x2

Q&D Indo 3.75+ AS03B x2

Q&D Indo 3.75+ AS03A x2

Q&D Indo 3.75+ AS03B x2

HI

GM

T

Risi et al., Vaccine 2011; 29:6408-18. E-23

Q-QIV-006 Vaccine Efficacy by Sub-Type/Lineage

(Total vaccinated cohort – post hoc exploratory analysis)

Event Group

AR VE

95% CI 95% CI

N n % LL UL T/N % LL UL

Moderate to severe - Type A

Q-QIV 2584 8 0.31 0.13 0.61 5.1 82.04 61.87 91.55

HAVRIX 2584 44 1.70 1.24 2.28 5.0

Moderate to severe - H1N1

Q-QIV 2584 4 0.15 0.04 0.40 5.1 79.10 38.58 92.89

HAVRIX 2584 19 0.74 0.44 1.15 5.0

Moderate to severe - H3N2

Q-QIV 2584 4 0.15 0.04 0.40 5.1 84.27 54.81 94.53

HAVRIX 2584 25 0.97 0.63 1.42 5.1

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

Q-QIV-006 Immunogenicity Geometric Mean Titer 28 Days After Vaccination

(ATP immunogenicity subset)

PR

E

PO

ST

PR

E

PO

ST

PR

E

PO

ST

PR

E

PO

ST

Flu A/CAL/7/09 (H1N1) Flu A/Victoria/210/09 (H3N2)

FluB/Bri/60/08 (Victoria) Flu B/Florida/4/06 (Ya-magata)

10

100

1000

15.3

318.8

24.3

264.7

13.7

239.9

16.2

361.5

16.1 16.1

28.6 30.3

15.617.8 18.8 19.2

Ge

om

etr

ic m

ea

n t

itre

s

Q-QIV Havrix™ ControlE-30

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

18-64 64+ 18-64 64+H1N1 H1N1 H5N1 H5N1

0.0

0.5

1.0

1.5

2.0

2.5

3.0

2.57

2.12

2.40

1.91

Post-Vaccination Log10 GMT w/ 95% CI

18-64 64+ 18-64 64+H1N1 H1N1 H5N1 H5N1

0%

20%

40%

60%

80%

100%90.1%

78.2%

90.8%

74.0%

Seroconversion Rate w/ 95% CI

65+ 65+ 65+ 65+

E-35

Q-Pan H5N1-021: HI Responses

PRE (n=182)

PI(D21) (n=179)

PII(D42) (n=175)

PRE (n=184)

PI(D21) (n=184)

PII(D42) (n=185)

PRE (n=204)

PI(D21) (n=204)

PII(D42) (n=203)

6M-<36M 3Y-<9Y 9Y-<18Y

1

10

100

1000

5.3

38.7

777.1

5.6

44.6

543.8

5.7

35.3

416.2

GM

Ts

wit

h 9

5%

CI

SCR: 57.5% 100% 58.5% 99.5% 51.5%99.0%

E-43

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

All

Gra

de 3 All

Gra

de 3 All

Gra

de 3 All

Gra

de 3 All

Gra

de 3 All

Gra

de 3 All

Gra

de 3 All

Gra

de 3 All

Gra

de 3 All

Gra

de 3 All

Gra

de 3 All

Gra

de 3

6M-<36M 3Y-<9Y 9Y-<18Y 6M-<36M 3Y-<9Y 9Y-<18Y 6M-<36M 3Y-<9Y 9Y-<18Y 6M-<36M 3Y-<9Y 9Y-<18YQ Pan Saline Q Pan Saline

Dose 1 Dose 2

0

10

20

30

40

50

60

70

80

90

100Incidence of pain per dose/per age stratum

E-44

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

All

≥3

8.5

≥3

9.0

≥3

9.5

>4

0.0 All

≥3

8.5

≥3

9.0

≥3

9.5

>4

0.0 All

≥3

8.5

≥3

9.0

≥3

9.5

>4

0.0 All

≥3

8.5

≥3

9.0

≥3

9.5

>4

0.0 All

≥3

8.5

≥3

9.0

≥3

9.5

>4

0.0 All

≥3

8.5

≥3

9.0

≥3

9.5

>4

0.0 All

≥3

8.5

≥3

9.0

≥3

9.5

>4

0.0 All

≥3

8.5

≥3

9.0

≥3

9.5

>4

0.0

6M-<36M 3Y-<6Y 6M-<36M 3Y-<6Y 6M-<36M 3Y-<6Y 6M-<36M 3Y-<6YQ Pan Saline Q Pan Saline

Dose 1 Dose 2

0

2

4

6

8

10

12

14

Incidence fever per dose in children < 6 years

E-45

Quebec* and Dresden* Manufacturing Processes

Downstream Process & Formulation

Quebec Dresden

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

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

-PAN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Q-P

AN

Plac

ebo

Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Dose 1 Dose 2

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

69.2

13.8

74.6

6.9

55.0

4.4

29.3

2.3

12.7

1.16.3

1.13.7

0.4

67.2

9.2

66.8

6.0

44.6

2.5

20.1

1.6

8.4

0.83.7

0.5 2.3 0.4

1.7

0.3

2.4

0.0

1.4

0.0

0.6

0.1

0.3

0.1

0.1

0.00.0

0.0

2.1

0.1

1.9

0.1

0.8

0.3

0.4

0.1

0.1

0.00.0

0.00.0

0.0

Percentage of subjects who reported Pain

Grade3

Any

Pe

rce

nta

ge

of

Su

bje

cts

S-5

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

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

Age (years), gender

AIH Diagnostic

Score

Comments

14, F 3 Concurrent cholecystitis and E. coli bacteremia

10, F 6 Severe acne, family h/o lupus

17, F 0 JRA with renal involvement

65, F 3 h/o bile duct surgery

14, F 7 Abdominal pain, nausea and cold sweat 7 mos prior to vaccination

Definite AIH: score 7; Probable AIH: score 6

S-16

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 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)

29 13 Non-adjuvanted Overall: 4.4 (1.3 – 14.2)

Wise, 2012 (USA)

Cohort 411 29Non-

adjuvantedOverall: 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

(<18 - 65+)5 3

Non-adjuvanted Overall: 2.5 (0.42 – 15.0)

S-34

Adjuvanted H1N1 Vaccine Postmarketing Studies: Guillain-Barré Syndrome (GBS)

Author(country)

Study design (Age range)

N Cases

N Exposed Adjuvant

ORoverall + age stratified

95% CI

Andrews, 2011 (UK)

SCCS (0 – 70+)

327 37 ASO3 Overall: 1.15 (0.45–2.49)

Grimaldi-Bensouda, 2011 (FR)

Case-control(4 – 79)

145 2ASO3 + Non Adj

0.92 (0.11 – 7.55)

Bardage, 2011 (SE)

Cohort - 39 ASO3 Overall: 1.07 (0.66 – 1.74)

De Wals, 2012 (Canada)

SCCS(1 – 89)

83 42ASO3

Overall: 1.95 (1.05 – 3.63)

Dieleman, 2011(5 EU—VAESCO )

Case-control(< 18 – 60+)

104 29ASO3

+MF-59Pooled: 1.0 (0.3 – 2.7)

WeibelGlobal

Meta-analysis1,163 253

ASO3 +MF-59

+ Non Adj

Pooled: 1.7 (1.3 – 2.1)

Pooled Adj (UK, EU, CA, Fr, SE): 1.3(0.9 – 1.8)

Pooled non-Adj (USA): 1.9 (1.4 — 2 .6)

SCCS= Self controlled case series S-35

SOTR: Results of selected, published studiesStudy size Outcome Reference

216 SOTR 138 controls

No increase in incidence of graft rejection Siegrist 2012

151 kidney TR Anti-HLA antibodies in 17.3% and 11.9% (2 cohorts) vs. 6% in historical controls (seasonal TIV); transient, no change in graft function

Katerinis 2011

111 kidney TR No change in anti-HLA I/II antibody prevalence Broeders 2011

47 heart TR No clinical graft rejection Meyer 2011

15 heart TR60 controls

No clinical graft rejection, increase in cellular rejection on biopsies (small numbers, limited adjustment for confounding)

Schaffer 2011

168 lung TR No rejection events reported Schuurmans 2011

107 kidney TR 5.6% de novo DSA, comparable to seasonal flu vaccine; 2 humoral rejections with graft loss (no unvaccinated controls)

Brakemeier 2011

5 heart TR No clinical evidence of rejection after 6 months follow-up Altamirano 2011

127 liver Similar % of AEs in vaccinated transplant recipients and healthy controls. No clinical rejection

Goldschmidt 2011

79 kidney No rejection events reported Crespo 2011

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Documents

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