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Prevnar 13 for Adult Use (Age >50 Years)(Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein)

Applicant: Wyeth Pharmaceuticals, Inc.

Rosemary Tiernan, MD, MPH

Division of Vaccines and Related Products Applications

CBER/FDA

Vaccines and Related Biological Products Advisory Committee Meeting

November 16, 2011

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Overview of Safety Presentation

• Studies Supporting Safety in Adults Age > 50 yrs• Safety Population • Safety Monitoring and Data Collection• Adverse Reactions • Summary/Conclusions

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Six Phase 3 Studies Supported Safety of PCV13 in Adults Study Site Age (Yrs) Schedule and ( # Vaccinated)

004Naive

USA60-64

50-59

Initial Study: Extension (3-4.5yrs):

Cohort 1 PCV13 (417) PCV13/PCV13 (108)

PCV13/23vPS (108)

Cohort 1 23vPS (414) 23vPS/23vPS (189)

Cohort 2 PCV13 (404) PCV13/PCV13 (214)

3000>1 dose 23vPS > 3 yrs prior

USA, GER

Sweden

> 68 1 dose of PCV13 (1049)

3001Naive

USA 50-59 Group 1 PCV13 + TIV / Placebo (551-538)

Group 2 Placebo + TIV / PCV13 (560-543)

30051 dose 23vPS

> 5 yrs prior

USA, Sweden

> 70 Group 1 PCV13 (463) Year 0

Group 2 23vPS (473)

Group 1.1 PCV13 / PCV13 (391) Year 1

Group 2.1 23vPS / PCV13 (404)

3008Naive

GER, NETH

BELG, HUNG> 65 Group 1 PCV13 + TIV / Placebo (577-

560)

Group 2 Placebo + TIV / PCV13 (575-558)

3010Naive

USA 60-64 Group 1 PCV13 (478 ) Year 0

Group 2 23vPS (237)

Group 1.1 PCV 13 / PCV 13 (161) Year 1

Group 1.2 PCV13 / 23vPS (266)

Group 2.1 23vPS/ PCV13 (223)

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Safety Population

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Demographics Demographic Factors (N = 6198) PCV13 (N = 5667)

Age (Years) 50 - 93 50-64 2616 (46.2)

65-69 646 (11.4)

70-74 1139 (20.1)

75-79 760 (13.4)

> 80 506 (8.9)

Gender

Female 50.2 - 61.8%*

Race/Ethnicity

White > 91%

Black or African American 0.2 - 7.5%

Hispanic or Latino 0.6 - 4.8%

Asian 0.0 - 1.7%

Native Hawaiian or other Pacific Islander

<1%

American Indian <1%

Alaskan Native <1%

Other <1.4%

*Study 3005 Males (50.3-52.3%)

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Study Populations

Pre-existing underlying diseases included if condition was “stable”: • Disease not requiring significant change in therapy or hospitalization for worsening

disease for 12 weeks before receipt of study vaccine• Change to new therapy allowed if not caused by worsening disease • Change in dose or therapy within category allowed

Key Exclusion Criteria included: • Receipt of diphtheria-tetanus toxoid containing vaccines within 6 months of study

vaccine • Streptococcus pneumoniae infection documented w/in past 5 years• Impairment of immunological function:

– Immunoglobulin deficiencies, hematological malignancies, known HIV infection, collagen vascular disorders and subjects receiving immunosuppressive therapy

– If systemic corticosteroids administered short term for treatment of acute illness, subjects excluded from vaccination until corticosteroid therapy had been discontinued for at least 30 days.

• Serious chronic disorders:– Metastatic malignancy, severe chronic obstructive pulmonary disease, end-stage

renal disease, clinically unstable cardiac disease, or any other disorder that in investigator’s opinion precluded subject from participating in study.

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Underlying Medical Conditions in PCV13 Recipients (at 1st Dose)

Medical

ConditionsVaccine Naïve Pre-immunized

Study 3001 004 3010 3008 3000 3005

Age

(Yrs)

50-59 50-59 60-64 60-64 > 65 > 68 >70

N=1094

%

N=403

%

N=417

%

N=478

%

N=1134

%

N=1049

%

N=463

%

Cardiac 2.7 2.2 4.3 5.9 16.1 21.2 18.4

Pulmonary 8.0 8.7 8.9 9.4 22.2 26.2 13.0

Diabetes 8.4 8.2 8.4 15.3 16.2 19.7 15.3

Renal 0.3 0.0 0.2 0.2 1.2 5.0 5.2

Liver 0.7 0.0 0.2 0.4 0.4 0.8 0.9

Asthma 6.0 7.2 5.5 6.5 8.8 12.6 6.3

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Safety Data Collection and Monitoring

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Solicited Adverse Events

• Local and systemic reactions monitored daily for 14 days: – Electronic diary cards used to record information

– Local events included• Redness, swelling, pain, limitation of motion (LOM)

– Systemic events included:

• Fever measured using oral digital thermometer daily (at bedtime and whenever fever suspected)

• Fatigue, headache, chills, rash, vomiting, decreased appetite, new generalized muscle pain, aggravated generalized muscle pain, new generalized joint pain and aggravated generalized joint pain

– Data regarding medications to treat pain and fever collected in all studies, except study 004.

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Analysis of Adverse Events (AEs)

• Solicited Local and Systemic AEs– Vaccine Naïve– Pre-immunized

• Unsolicited Adverse Events• Deaths• Discontinuations due to Adverse Event• Serious Adverse Events (SAES)

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Vaccine Naïve SubjectsStudies 004 and 3010

• Solicited Local Adverse Reactions• Solicited Systemic Adverse Reactions

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Local Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve)

Local

ReactionsSTUDY 004 STUDY 3010

PCV13 PCV13 23vPS PCV13 23vPS

50-59 yrs 60-64 yrs 60-64 yrs 60-64 yrs 60-64 yrs

N=136-322

%

N=178-193

%

N=179-301

%

N=258-370

%

N=127-134

%

Redness

Any 15.8 20.2 14.2 12.2 11.2

Severe 0.7 1.7 0 1.2 0.8

Swelling

Any 21.7 19.3 13.1 10 10.4

Severe 0 0.6 1.1 0 0

Pain

Any 89 80.1 73.4 69.2 58.3

Severe 3.6 1.7 8.6 2.3 0.8

Limitation of Motion

Any 40.7 28.5 30.8 23.5 28.2

Severe 2.9 1.7 4.3 1.1 2.3

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Systemic Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve)Systemic Reactions

STUDY 004 STUDY 3010

PCV13 PCV13 23vPS PCV13 23vPS

50-59 yrs 60-64 yrs 60-64 yrs 60-64 yrs 60-64 yrs

N=144-248

%

N=180-277

%

N=185-273

%

N=261-328

%

N=127-173

%

Any Fever

(>38C)1.5 7.7 5.9 4.2 1.6

Fatigue 63.3 63.2 61.5 50.5 49.1

Headache 65.9 54.0 54.4 49.7 46.1

Chills 19.6 23.5 24.1 19.9 26.9

Rash 14.2 16.5 13.0 8.6 13.4

Vomiting 6.9 3.9 5.4 3.1 3.1

Decreased Appetite

25.3 21.3 21.7 14.7 23.0

New Myalgia

61.8 56.2 57.8 46.9 51.5

Aggravated Myalgia

39.9 32.6 37.3 22.0 32.5

New Joint Pain

31.5 24.4 30.1 15.5 23.8

Aggravated Joint Pain

25.6 24.9 21.4 14.0 21.1

Pain Meds N/A N/A N/A 31.3 32.7

Fever Meds N/A N/A N/A 8.6 17.5

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Summary on Reactogenicity in Naïve Subjects

• Local Reactogenicity – Study 004

• PCV 13 >23vPS for “any” redness/swelling/pain• 23vPS >PCV13 for “severe” pain (8.6% > 1.7-3.6%)

– Study 3010• PCV13 >23vPS for “any” pain (69.2 % vs 58.3%)

• Systemic Reactogenicity – Study 004

• PCV13 vs 23vPS similar incidences of systemic reactions– Study 3010

• 23vPS>PCV13 for decreased appetite, aggravated muscle pain, new joint pain, use of medication to treat fever

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Pre-Immunized SubjectsStudies 3000 and 3005

• Solicited Local Reactions• Solicited Systemic Reactions

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Local Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized)

Local

Reactions

Study 3000 ( > 68 yrs. ) Study 3005 ( > 70 yrs)

> 1 dose 23vPS > 3 yrs prior 1 dose 23vPS > 5 yrs prior

PCV13 PCV13 23vPS

N=634-777

%

N=297-362

%

N=306-383

%

Redness

Any 14.3 10.8 22.2

Severe 1.1 1.7 4.8

Swelling

Any 12.8 10.4 23.1

Severe 0.6 0.0 4.8

Pain

Any 51.0 51.7 58.5

Severe 0.2 1.3 2.3

Limitation of Motion

Any 16.2 10.5 27.6

Severe 1.6 0.7 3.0

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Systemic Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized)

Systemic

Reactions

Study 3000 ( > 68 yrs. )

> 1 dose 23vPS > 3 yrs prior

Study 3005 ( > 70 yrs)

1 dose of 23vPS > 5 yrs prior

PCV13 PCV13 23vPS

N= 638-733

%

N=297-350

%

N=301-367

%

Any Fever(>38C) 2.0 1.0 2.3

>40C 0.9 0.0 0

Fatigue 34.4 34.0 43.3

Headache 26.1 23.7 26.0

Chills 7.5 7.9 11.2

Rash 8.4 7.3 16.4

Vomiting 0.9 1.7 1.3

Appetite Decreased 11.2 10.4 11.5

New Myalgia 25.3 36.8 44.7

Aggravated Myalgia 12.3 20.6 27.5

New Joint Pain 12.8 12.6 14.9Aggravated Joint Pain 9.7 11.6 16.5

Pain Meds 17.0 22.0 26.6

Fever Meds 6.4 3.0 6.2

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Summary of Reactogenicity: Pre-Immunized Subjects

• Local Reactogenicity – Study 3005

• 23vPS > PCV13 for all local reactions

• Systemic Reactogenicity – Study 3005

• 23vPS >PCV13 for fatigue, rash, new muscle pain (myalgia), aggravated muscle pain

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Reactogenicity of Sequential Vaccine Administration (Studies 004 and 3010)

• Single dose 23vPS (naïve) compared to: – PCV13 /23vPS

• 1 year interval (study 3010)• 3-4 year interval (extension study 004)

– 23vPS / 23vPS administered at • 3-4 year interval (extension study 004)

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Local Reactogenicity within 14 days Post Dose

Local Reactions

60-64 Yrs

STUDY 004 STUDY 3010

Year 0 Year 3.5 - 4 Year l Year 0

23vPS* PCV13 / 23vPS 23vPS/ 23vPS PCV13 / 23vPS 23vPS*

N=185-301

%

N=41-87

%

N=82-164

%

N=131-231

%

N=127-175

%

Redness

Any 14.2 27.5 35.8 27.8 11.2

Severe 0 2.4 10.6 6.9 0.8

Swelling

Any 13.1 20.4 35.6 25.8 10.4

Severe 1.1 2.4 7.3 6.1 0

Pain

Any 73.4 83.9 84.8 85.7 58.3

Severe 8.6 9.1 11.6 12.9 0.8

Limitation of Motion

Any 30.8 42.1 48.2 53.4 28.2

Severe 4.4 4.9 9.5 8.1 2.3

23vPS* administered at Year 0 was 3-4.5 years prior in Study 004 and was 1 year prior in Study 3010.

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Systemic Reactogenicity within 14 days Post Dose

Systemic Reactions

Age

60-64 Yrs

STUDY 004 STUDY 3010

Year 0 Year 3.5-4 Year 1 Year 0

23vPS* PCV13 / 23vPS 23vPS/ 23vPS PCV13 / 23vPS 23vPS*

N=85-273

(%)

N=43-68

(%)

N=79-136

(%)

N=129-196

(%)

N=127-173

(%)

Any Fever(>38C) 5.9 4.7 2.5 3.1 1.6

Fatigue 61.5 63.2 57.6 51.9 49.1

Headache 54.4 50.0 54.2 49.7 46.1

Chills 24.1 33.9 34.3 29.0 26.9

Rash 13.0 18.4 32.6 24.0 13.4

Vomiting 5.4 4.7 1.3 4.6 3.1

Decreased Appetite

21.7 31.5 23.7 17.0 23.0

New Myalgia 57.8 65.2 67.6 61.2 51.5

Aggravated Myalgia

37.3 41.4 39.6 41.5 32.5

New Joint Pain 30.1 24.5 23.1 25.5 23.8

Aggravated Joint Pain

21.4 22.4 17.6 17.5 21.1

Pain Meds N/A N/A N/A 46.2 32.7

Fever Meds N/A N/A N/A 17.4 17.5

23vPS* administered at Year 0 was 3-4.5 years prior for Study 004 and was 1 year prior for Study 3010.

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Summary on Reactogenicity: Sequential Doses

• Solicited Local – Using a dosing interval of 3-4 yrs (extension study 004):

• 23vPS/23vPS is more reactogenic than PCV13/23vPS for redness, swelling and limitation of motion

– Using a dosing interval of 1 year (study 3010):• PCV13/23vPS is more reactogenic than 23vPS alone

• Solicited Systemic– Using a dosing interval of 3-4 yrs, 23vPS/23vPS is more

reactogenic for rash when compared to 23vPS alone– Using a dosing interval of 1 yr, PCV13/23vPS is more

reactogenic for rash and use of pain medications when compared to 23vPS alone

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Reactogenicity of Concomitant Administration ofPCV13 with Trivalent Influenza Vaccine (TIV)

Studies 3001 and 3008

Solicited Adverse Reactions for PCV13 + TIV compared to PCV13: – Local– Systemic

Reactogenicity of Concomitant Administration of PCV13 with TrivalentInfluenza Vaccine (TIV) in a Pneumococcal Vaccine Naïve Population:Design for Studies 3001 and 3008

Study Arms Concomitant Dose 1 Dose 2

(1 month later)

Group 1 PCV13 + TIV Placebo

Group 2 Placebo + TIV PCV13

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Local Reactogenicity (PCV13+TIV vs PCV13) within 14 Days (Naïve)

Study 3001 (age 50-59 yrs) Study 3008 ( age > 65 yrs)

Local

Reactions

PCV13 +TIV / Placebo

Concomitant Dose 1

Placebo +TIV / PCV13

Dose 2

PCV13 +TIV/ Placebo

Concomitant Dose 1

Placebo +TIV/ PCV13

Dose 2

N=266-317

%

N=241-453

%

N=429-480

%

N=420-470

%

Redness

Any 16.3 12.1 16.6 12.3

Severe 0.4 1.2 0.7 1.0

Swelling

Any 18.4 14.7 13.8 10.2

Severe 0.4 0.4 0.2 0

Pain

Any 86.8 84.5 40.0 43.4

Severe 4.1 4.8 1.4 2.6

Limitation of Motion

Any 35.6 42.5 13.9 14.8

Severe 3.4 2.9 1.9 1.4

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Systemic Reactogenicity (PCV13 + TIV vs PCV13) within 14 Days (Naive)

Systemic

ReactionsStudy 3001

(Age 50-59 yrs)

Study 3008

(Age > 65 yrs)

PCV13 +TIV /Placebo

Concomitant Dose 1

Placebo +TIV /PCV13

Dose 2

PCV13 +TIV /Placebo

Concomitant Dose 1

Placebo +TIV /PCV13

Dose 2

N =266-399%

N=247-350%

N=432-476%

N=428-456%

Any Fever(>38C)

3.4 2.5 5.8 4.7

Fatigue 58.1 51.8 37.4 28.5

Headache 65.9 50.9 32.6 24.7

Chills 31.4 24.6 13.8 9.1

Rash 12.6 9.5 6.9 6.8

Vomiting 5.3 6.1 3.0 1.7

Appetite

Decreased30.2 25.8 16.9 11.3

New Myalgia 65.5 59.1 26.9 23.4

Aggravated Myalgia

34.7 36.7 18.7 15.0

New Joint Pain 33.0 27.4 16.2 11.5

Aggravated Joint Pain

21.2 23.8 15.7 8.6

Pain Meds 39.3 32.8 N/A N/A

Fever Meds 22.8 18.8 N/A N/A

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Reactogenicity of Concomitant Administration ofPCV13 with Trivalent Influenza Vaccine (TIV)

Studies 3001 and 3008 (Naïve)

Solicited Adverse Reactions for PCV13 + TIV compared to Placebo +TIV: – Local– Systemic

Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) in a Pneumococcal Vaccine Naïve Population: Design for Studies 3001 and 3008

Study Arms Concomitant Dose 1 Dose 2

(1 month later)

Group 1 PCV13 + TIV Placebo

Group 2 Placebo + TIV PCV13

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Local Reactogenicity (PCV13+TIV vs TIV+ Placebo) within 14 Days (Naïve)

Local

ReactionsStudy 3001

(Age 50-59 yrs)

Study 3008

(Age > 65 yrs)

PCV13 +TIV / Placebo

Concomitant Dose 1

Placebo +TIV / PCV13

Concomitant Dose 1

PCV13 +TIV /Placebo

Concomitant Dose 1

Placebo +TIV / PCV13

Concomitant Dose 1

N=262-324

%

N=257-325

%

N=429-480

%

N=420-470

%

Redness

Any 16.3 3.0 16.6 12.3

Severe 0.4 0.0 0.7 1.0

Swelling

Any 18.4 3.0 13.8 10.2

Severe 0.4 0.0 0.2 0.0

Pain

Any 86.8 37.1 40.0 43.4

Severe 4.1 0.4 1.1 2.6

Limitation of Motion

Any 35.6 8.9 13.9 14.8

Severe 3.4 0.8 1.9 1.4

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Systemic Reactogenicity (PCV13 + TIV vs TIV+ Placebo) within 14 Days (Naive)

Systemic

ReactionsStudy 3001

(Age 50-59 yrs)

Study 3008

(Age > 65 yrs)

PCV13 +TIV /Placebo

Concomitant Dose 1

Placebo +TIV /PCV13

Concomitant Dose 1

PCV13 +TIV /Placebo

Concomitant Dose 1

Placebo +TIV /PCV13

Concomitant Dose 1

N =261-389%

N=257-382%

N=-428-476%

N=420-456%

Any Fever(>38C)

3.4 1.2 5.8 4.7

Fatigue 58.1 52.4 37.4 31.9

Headache 65.9 56.5 32.6 29.7

Chills 31.4 21.0 13.8 9.1

Rash 12.6 4.9 6.9 3.4

Vomiting 5.3 3.4 3.0 3.4

Appetite

Decreased30.2 22.6 16.9 14.6

New Myalgia 65.5 37.7 26.9 16.7

Aggravated Myalgia

34.7 24.1 18.7 14.0

New Joint Pain 33.0 24.7 16.2 13.1

Aggravated Joint Pain

21.2 18.0 15.7 13.0

Pain Meds 39.3 24.5 10.7 10.5

Fever Meds 22.8 13.9 4.8 5.0

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Summary of Reactogenicity for Concomitant Administration of PCV13 +TIV compared to PCV13 and TIV+ Placebo:

Studies 3001 and 3008 (Naïve)

• Solicited Local Reactogenicity– Study 3001 (age 50-59 yrs)

• PCV13 (42%) > PCV13+TIV (35.6%) for “any” limitation of motion• PCV13 +TIV > TIV for all local reactions

• Solicited Systemic Reactogenicity – Incidence of “any” fever (>38C) not increased with concomitant

administration of PCV13+TIV compared to PCV13 or TIV + placebo in studies 3001 and 3008.

– In study 3001 and 3008, when compared to PCV 13 or TIV+ placebo, PCV13+ TIV study arm had a higher incidence of these AEs:

• Fatigue• Headache• Chills• Rash• Decreased appetite• New and aggravated muscle pain• New joint pain• Aggravated joint pain

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Unsolicited Adverse Events within 1 Month

• Incidence across 6 studies for PCV13 was 11.4 -19.2%• Similar incidence in naïve and pre-immunized subjects• Similar incidence for initial dose of PCV13 when compared to

23vPS in naïve and pre-immunized subjects:– Naïve subjects

• Study 004 (60-64 yrs)– PCV 13 (17.0%) vs 23vPS (16.7 %)

• Study 3010 (60-64 yrs)– PCV 13 (19.2%) vs 23vPS (20.7 %)

– Pre-immunized subjects• Study 3005

– PCV13 (14.9 % ) vs 23vPS (18.6%)• Most frequent AEs reported for PCV13:

– Infections and Infestations (4.1-8.6%)– Musculoskeletal (1.6-4.1%)– Gastrointestinal (1.2-2.6%)– General disorders and administration site conditions (0.6-3.1%)

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Summary of 16 Deaths Across 6 Studies

Study Vaccine Administered Last Dose

Days Post-Dose

Age at Death (Yrs)

MedDRA Term

3008 PCV13 +TIV / Placebo 2 3 72 Cardiac Failure

3008 Placebo +TIV / PCV13 2 20 69 Peritonitis

3001 PCV13 +TIV / Placebo 2 71 55 Hemoptysis

3005 23vPS 1 72 85 Post-Procedure Pulmonary Embolus

3005 PCV13 / PCV13 2 85 84 Atherosclerotic coronary artery disease

3005 PCV13 1 104 71 Myocardial Infarction

3005 PCV13 1 135 87 Cardiac Arrest

3005 23vPS 1 141 75 Cardiac Failure Congestive

3000 PCV13 1 146 69 Metastatic Neoplasm

3000 PCV13 1 186 79 Septic Shock

3000 PCV13 1 192 71 Lung Neoplasm Malignant

3005 PCV13 1 200 79 Colon Cancer

004 PCV13 1 224 63 Hepatic neoplasm Malignant, Pancreatic carcinoma, Thrombosis

3005 23vPS 1 256 77 Acute Myocardial Infarction

3005 23VPS 1 262 86 Cardiac Arrest

3005 PCV13 1 309 81 Atherosclerotic coronary artery disease

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Deaths (Across 6 Studies)

16 subjects died:• 2/16 deaths occurred within 30 days of vaccination

– Cardiac Failure at 3 days after PCV13+TIV / Placebo– Peritonitis at 20 days after Placebo+TIV / PCV13

• 9/16 in study 3005– Subjects ≥70 years of age

• 12/5667 (0.21%) received PCV13 or PCV13+TIV• 4/1391 (0.29%) subjects received 23vPS

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Summary of 16 Adverse Events leading to Discontinuation (6 Studies)

Study Vaccine Administered

Last Dose

Days

Post-Dose

Severity MedDRA Term

3001 Placebo +TIV 1 1 Moderate Fatigue and Headache

3005 PCV13 / PCV13 2 9 Severe Worsening of COPD

3008 PCC13 +TIV/ Placebo

2 10 Life-threatening Angina pectoris, ECG

ST segment elevation

3005 23vPS 1 23 Severe Prostate cancer

3010 23vPS 1 28 Severe Unstable Angina

3010 23vPS 1 39 Life-threatening Malignant Melanoma

3005 23vPS 1 135 Moderate Hyperthyroidism, Mental Status Changes

3005 23vPS 1 154 Severe Prostate cancer

3005 PCV13 1 174 Severe Metastatic prostate cancer/bone

3005 23vPS 1 235 Moderate Polymyalgia

3005 PCV13 1 274 Life-threatening Cerebral Infarction

3005 23vPS 1 284/297 Severe / Moderate

Atrial Flutter, Congestive Heart Failure / Pneumonia and Pericardial/pleural effusion status post drainage

004 23vPS 1 290 Severe Lung cancer metastatic

3005 PCV13 1 323 Moderate Abdominal Pain Upper

3005 PCV13 1 329 Moderate Bladder Neoplasm

3005 23vPS 1 365 Severe Adenocarcinoma

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Adverse Events leading to Discontinuation(Across 6 Studies)

• 16 subjects discontinued due to adverse events– 7 of 16 subjects discontinued due to cancer

• 6 of 16 subjects received PCV13• 9 of 16 subjects received 23vPS• 1 of 16 subjects received TIV +placebo

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Incidence of Serious Adverse Events after Initial Dose (6 Studies)

Subjects with SAEs Within 1 month n (%) Within 6 months n (%)

Naïve Subjects:

Study 004 Initial Dose

PCV13 ( N= 417) (60-64 yrs) 1 (0.2) 12 (2.9)

23vPS (N= 414) 2 (0.5) 10 (2.4)

PCV13 (N= 403) (50-59yrs) 2 (0.5) 5 (1.2)

Study 3010 (60-64 yrs) Initial Dose

PCV13 (N= 478) 2 (0.4) 15 (3.1)

23vPS (N= 237) 1 (0.4) 6 (2.5)

Study 3001 (50-59 yrs)

PCV13+TIV / Placebo (N=551 / 538) 4 (0.7) / 3 (0.6) 18 (3.3)

Placebo+TIV / PCV13 (N= 560 / 543) 5 (0.9) / 6 (1.1) 10 (1.8)

Study 3008 (>65 yrs)

PCV13+TIV / Placebo (N= 576) 4 (0.7) / 5 (0.9) No 6 month follow-up

Placebo+TIV / PCV13 (N=575) 0 (0) / 8 (1.4) No 6 month follow-up

Pre-Immunized Subjects:

Study 3000 ( > 68 yrs)

PCV13 (N = 1049) 10 (1.0) 41 (3.9)

Study 3005 ( >70 yrs) (Initial Dose)

PCV13 (N= 463) 3 (0.6) 27 (5.8)

23vPS (N= 473) 8 (1.7) 26 (5.5)

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Serious Adverse Events (Initial Dose, 6 Studies)

• SAE range within 1 month of vaccination:– 0.2% to 1.4% of PCV13 recipients – 0.4% to 1.7% of 23vPS recipients.

• SAE range within 6 months of vaccination:– 1.2% to 5.8% of PCV13 recipients– 2.4% to 5.5% of 23vPS recipients

• Categories of SAE:– Age > 65 years

• Cardiac disorders, cerebrovascular events, neoplasms, respiratory disorders and injuries occurred more frequently than in younger subjects

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Incidence of Serious Adverse Events after Subsequent Dose (3 Studies)

Subjects with SAEs Within 1 month n (%) Within 6 months n (%)

Naïve Subjects:

Study 004 Extension Study (Year 3-4)

PCV13/ PCV13 (N =108) (60-64 yrs) 1(.01)* N/A

PCV13/ 23vPS (N=108) 1(.01) N/A

23vPS/ 23vPS (N=189) 0 (0) N/A

PCV13 / PCV13 (N=214 ) (50-59yrs) 0 (0) N/A

Study 3010 (Year 1)

PCV13/ PCV13 (161) (60-64 yrs) 0 (0) 5 (3.1)

PCV13/ 23vPS (266) 2 (0.7) 6 (2.2)

23vPS / PCV13 (223) 1 (0.4) 3 (1.3)

Pre-Immunized Subjects:

Study 3005 (Year 1)

PCV13/ PCV13 (N= 391) (>70 yrs) 4 (1.0) 17 (4.3)

23vPS/ PCV13 (N= 404) 7(1.7) 21 (5.2)

*Erythema multiforme at day 34.

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Conclusions Regarding Safety• In 6 clinical studies, which included vaccine naïve and adult subjects with prior receipt of

PNEUMOVAX23, no imbalances in deaths or serious adverse events were detected in subjects who received Prevnar13 when compared to PNEUMOVAX23.

• No safety issues were identified for administration of Prevnar13, as a single dose, to vaccine naïve or pre-immunized adults aged > 50 years

– the safety database is not large enough to detect rare events that could occur at a frequency lower than

0.1%.

• When Prevnar13 was concomitantly administered with TIV, systemic reactogenicity was increased in subjects aged 50-59 yrs and subjects > 65 yrs when compared to administration of TIV or Prevnar13 alone.

• No data available for concomitant administration of Prevnar13 with adult vaccines other than TIV.

• No data available for use of Prevnar13 in immunocompromised adults.

• Safety data will be submitted from the randomized, placebo-controlled CAPITA trial of PCV13 for the prevention of vaccine type pneumococcal pneumonia conducted in 85,000 subjects aged > 65 years in the Netherlands. Safety data will include:

– SAEs in the 28 days post-vaccination for subjects not in the immunogenicity cohort– SAEs for 6 months post-vaccination for the 2000 subjects in the immunogenicity cohort– Incidence rates of local, systemic and adverse events for all subjects in the immunogenicity cohort.