Vaccines and Related Biological Products Advisory Committee Presentation on Sanofi Pasteur’s H5N1...

Vaccines and Related Biological Products Advisory Committee Presentation on

Sanofi Pasteur’s H5N1 Vaccine

Andrea N. James, M.D.

Senior Medical Officer

Division of Vaccines and Related Product Applications

FDA VRBPAC Meeting 2

Presentation Outline

• Summary of the Product

• FUG01 Study Description

• FUG01 Immunogenicity Results

• FUG01 Safety Results

• BLA Summary

• Limitations of the Data

• Questions to the Committee


Summary of the Product

• BLA submission date: October 17, 2006

• Product: H5N1 Influenza Virus Vaccine, A/Vietnam/1203/2004 (clade 1)

• Proposed Dosage: 90 µg

• Proposed Administration: Two 1mL IM injections administered 28 days apart.


Summary of Product (cont)• Sanofi’s Proposed Indication: H5N1 Influenza

Virus Vaccine, A/Vietnam/1203/2004 (clade 1) 90μg/mL is an influenza viral vaccine indicated for:– Active immunization against influenza disease

caused by H5N1 A/Vietnam/1203/2004 (clade 1) influenza virus.

– Primary vaccination of healthy adults 18 through 64 years of age.

FUG01 Trial Design and Population Description


FUG01 Study Design

• FUG01• Phase I/II randomized, double blind, two-stage, placebo-

controlled, dose ranging study• Eligible subjects: healthy 18 – 64 years of age• Stratified by age (< or > 40 yrs) and prior seasonal

influenza vaccine (2004 – 2005 season) • Randomized 1:2:2:2:2 to 1 of 5 doses

– Saline placebo, 7.5 µg, 15 µg, 45 µg or 90 µg

• Placebo/vaccine administration: two 1mL intramuscular injections 28 days apart.


FUG01: Study Design

Study Objectives1) To determine the dose-related safety of subvirion

inactivated H5N1 vaccine in healthy adults.

2) To determine the dose-related immunogenicity of subvirion inactivated H5N1 vaccine in healthy adults approximately 1 month following receipt of 2 doses of vaccine.

3) To provide information for the selection of the best dose levels for further studies.


FUG01: Study Design

HAI Immunogenicity Endpoint Analyses• 4-fold or greater increases in serum HAI

antibody titers 28 days after receipt of each dose, and 6 months after receipt of the second dose of vaccine.

• > 1:40 serum HAI antibody titers 28 days after receipt of each dose, and 6 months after receipt of the second dose of vaccine.


FUG01: Study Description

• Exploratory study– Not statistically powered to provide

estimates of immunogenicity at any specific dose.

– Not statistically powered to detect rare safety events

• Results provide trends


FUG01 Subject Demographics and Baseline Characteristics

• Subjects enrolled = 452• Majority of subjects were

– Caucasian 80.8%– Females 53.5%

• Mean age of 40.5 years (range: 18.1 – 64.9 years)

• Majority of subjects (58.4%) had not received the 2004-2005 seasonal influenza vaccine

• 3.3% of all subjects had detectable H5 antibody at baseline

FUG01 Immunogenicity Results


FUG01: Percent of Per Protocol Subjects with 4-Fold HAI Titer Rise

4-Fold Rise in HAI titer%

PlaceboN=42

90 µgN=91

28 Days post Vaccination 195% CI

0

(0.0;8.4)23.1%

(14.9;33.1)


0(0.0;8.4)

45.1%(34.6;55.8)

6 Months post Vaccination 295% CI

2.4%

(0.1;12.9)

17.6%

(10.4;27.0)


FUG01: Percent of Subjects with 4-Fold HAI Titer Rise

95% CI of Percent of Subjects with 4 Fold Increase in HAI Antibody: Placebo vs 90 mcg

0

20

40

60

80

100

0 50 100 150 200 250Time (in days)

% R

es

po

nd

ers

Placebo (n=42)

90 mcg (n=91)

Day 0Baseline


FUG01 Dose Response : Percent of Subjects with 4-Fold HAI Titer Rise

4-fold Increase of HAI Titer

0

20

40

60

80

100

0 50 100 150 200 250

Time (in days)

% R

es

po

nd

ers

Placebo

7.5 ug15 ug

45 ug90 ug


FUG01: Percent of Subjects with HAI Titers > 1:40

HAI Titer > 1:40

%

PlaceboN=42

90 µgN=91

Baseline95% CI

0(0.0;3.8)

1.0%(0.0;6.0)


2.4%(0.1;12.6)

24.2%

(15.8;34.3)


2.4%

(0.1;12.6)46.0%

(35.6;56.9)

6 Months post Vaccination 295% CI

4.8%(0.6;16.5)

18.7%(17.3;28.2)


FUG01: Percent of Subjects with HAI Titers > 1:40

95% CI of Percent of Subjects with HAI Titers > 1: 40: Placebo vs 90 mcg

0

20

40

60

80

100

0 50 100 150 200 250

Time (in days)

% R

es

po

nd

ers

Placebo (n=42)

90 mcg (n=91)

Day 0Baseline

Additional Analyses

Gender

Race/Ethnicity

Age and Prior Influenza Strata


PP Gender Subgroup Analysis: Percent 4-Fold HAI Rise

90 µg

Males

N = 41

Females

N = 50

% Responders 46% 56%


PP Race/Ethnicity Subgroup Analysis: Percent 4-Fold HAI

Rise

90 ug

Caucasian

N = 76

Black

N = 9

Asian

N = 6

Hispanic

N = 11

%

Responders 51.3% 55.6% 50% 81.8%


Stratified Populations: 4-Fold Rise in HAI Titer

90 µg Group Age < 40 years

N = 48

Age > 40 years

N = 43

No 2004/05 Influenza Vaccine

N = 52

75%

(24/32)

35%

(7/20)

Received 2004/05 Influenza Vaccine

N = 39

37.5%

(6/16)

43.5%

(10/23)


Immunogencity Summary• This H5N1 vaccine appears to have a dose related

immune response.

• 90 µg dose appears to have a better response rate– ~45% of subjects responding after two doses of vaccine.

• Immunogenicity observed in this study is less than what is usually seen in seasonal influenza vaccine studies.

• The impact of gender, ethnicity and prior seasonal vaccination on H5 immunogenicity is unclear and may warrant further exploration.

H5N1 Safety Results


FUG01 Safety Assessments

• Frequency and incidence of – Immediate reactions

• 15 – 30 minutes post vaccinations.

– Solicited local and systemic reactions• Day 0 through Day 7 post vaccinations

– Unsolicited AEs and SAEs• Study Day 0 through Day 56


Safety Data Background

• Solicited injection site (local) AEs included:– Pain – Tenderness– Redness – Swelling


Safety Data Background (cont)

• Solicited systemic AEs included:– Feverishness – Malaise – Body aches (exclusive of the injection site)– Nausea – Headache


SAEs

• Four SAEs: none considered vaccine related• One death (45 µg arm)

– 52 y.o. male with h/o chronic alcoholism– Death secondary to sequelae of chronic

alcoholism

• Three other SAES– Breast cancer (placebo arm)– Menorrhagia (15 µg arm)– Cerebrovascular accident (90 µg arm)


Local Reactogenicity EventsPlacebo

N=487.5µgN=101

15 µgN=101

45 µgN=98

90 µgN=103

% Subjects with > 1 Injection Site AE(s)

45.8% 59.4% 68.3% 78.6% 84.5%

% Subjects with Moderate (Gr 2) Injection Site AEs

0 3.0% 5.0% 7.1% 13.9%

% Subjects with Severe (Gr 3) Injection Site AEs

0 0 0 0 0

# of Injection Site AEs 89 237 266 424 537

Pain 22.5% 21.9% 33.5% 35.1% 36.1%

Tenderness 21.3% 29.1% 34.2% 35.4% 35.2%

Erythema/Redness 34.8% 35.9% 23.3% 22.4% 18.2%

Induration/Swelling 21.3% 13.1% 9.0% 7.1% 10.4%


Systemic Reactogenicity EventsPlacebo

N=487.5µgN=101

15 µgN=101

45 µgN=98

90 µgN=103

% Subjects with > 1 Systemic AE(s)

58.3% 39.6% 47.5% 35.7% 47.6%

% Subjects with Moderate (Gr 2) Systemic AEs

20.8% 14.9% 20.8% 6.1% 11.7%

% Subject with Severe (Gr 3) Systemic AEs

0 1.0% 2.0% 0 1.0%

# of Systemic AEs 125 207 349 109 171

Headache 36% 33.8% 30.7% 40.4% 38.0%

Malaise 34.4% 27.5% 28.0% 28.4% 29.8%

Body aches 22.4% 21.3% 23.5% 19.3% 17.0%

Nausea 3.2% 9.7% 12.0% 6.4% 8.8%

Feverishness 4.0% 7.7% 5.7% 5.5% 6.4%


Safety Summary

• Dose dependent increase in frequency of local reactogenicity events– Pain and tenderness more common in the

90 µg group

• No other apparent safety signals


BLA Summary

BLA for H5N1 Influenza Virus Vaccine, A/Vietnam/1203/2004 (clade 1)– 90 µg– Two 1mL IM injections administered 28 days apart.

• Immunogenicity observed in study FUG01 is less than what is usually seen in seasonal vaccine studies. – ~45% of subjects responding after two doses of vaccine

• No apparent safety issues


Limitations of the Data

• Clinical database is small– Not statistically powered to detect rare adverse

events.– Not statistically powered to produce statistically

significant results.– Results provide trends only.

• Unknown clinical efficacy of this vaccine.• Unknown correlate of protection against H5.• Unknown impact of gender, ethnicity, and

prior seasonal influenza vaccination.

Questions to the Committee


Sanofi’s Proposed Indication

• H5N1 Influenza Virus Vaccine, A/Vietnam/1203/2004 (clade 1) 90μg/mL is an influenza viral vaccine indicated for:– Active immunization against influenza disease

caused by H5N1 A/Vietnam/1203/2004 (clade 1) influenza virus.

– Primary vaccination of healthy adults 18 through 64 years of age.


1. Are the data sufficient to support the effectiveness of this product for use during a pandemic or in situations of potential high risk exposure.


2. Are the data sufficient to support the safety of this product for use during a pandemic or in situations of potential high risk exposure.


3. Please comment on studies to collect additional information about the effectiveness and safety following this vaccine’s use.


Acknowledgement Slide

Tammy Massie, PhD

Melisse Baylor, MD

Antonia Gerber, MD

Joseph Toerner, MD, MPH

Douglas Pratt, MD

David Menschik, MD

Therese Cvetkovich, MD

Zhiping Ye, MD, PhD

Carmen Collazo, PhD

Rakesh Pandey, PhD

Marion Gruber, PhD

Mark Goldberger, MD, MPH

Florence Houn, MD

Norman Baylor, PhD

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