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 Meeting2 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

FDA VRBPAC Meeting3 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.

FDA VRBPAC Meeting4 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

FDA VRBPAC Meeting6 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 ( 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.

FDA VRBPAC Meeting7 FUG01: Study Design Study Objectives 1)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.

FDA VRBPAC Meeting8 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.

FDA VRBPAC Meeting9 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

FDA VRBPAC Meeting10 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 seasonal influenza vaccine 3.3% of all subjects had detectable H5 antibody at baseline

FUG01 Immunogenicity Results

FDA VRBPAC Meeting12 FUG01: Percent of Per Protocol Subjects with 4-Fold HAI Titer Rise 4-Fold Rise in HAI titer % Placebo N=42 90 µg N=91 28 Days post Vaccination 1 95% CI 0 (0.0;8.4) 23.1% (14.9;33.1) 28 Days post Vaccination 2 95% CI 0 (0.0;8.4) 45.1% (34.6;55.8) 6 Months post Vaccination 2 95% CI 2.4% (0.1;12.9) 17.6% (10.4;27.0)

FDA VRBPAC Meeting13 FUG01: Percent of Subjects with 4-Fold HAI Titer Rise

FDA VRBPAC Meeting14 FUG01 Dose Response : Percent of Subjects with 4-Fold HAI Titer Rise

FDA VRBPAC Meeting15 FUG01: Percent of Subjects with HAI Titers > 1:40 HAI Titer > 1:40 % Placebo N=42 90 µg N=91 Baseline 95% CI 0 (0.0;3.8) 1.0% (0.0;6.0) 28 Days post Vaccination 1 95% CI 2.4% (0.1;12.6) 24.2% (15.8;34.3) 28 Days post Vaccination 2 95% CI 2.4% (0.1;12.6) 46.0% (35.6;56.9) 6 Months post Vaccination 2 95% CI 4.8% (0.6;16.5) 18.7% (17.3;28.2)

FDA VRBPAC Meeting16 FUG01: Percent of Subjects with HAI Titers > 1:40

Additional Analyses Gender Race/Ethnicity Age and Prior Influenza Strata

FDA VRBPAC Meeting18 PP Gender Subgroup Analysis: Percent 4-Fold HAI Rise 90 µg Males N = 41 Females N = 50 % Responders46%56%

FDA VRBPAC Meeting19 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%

FDA VRBPAC Meeting20 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 = % (6/16) 43.5% (10/23)

FDA VRBPAC Meeting21 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

FDA VRBPAC Meeting23 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

FDA VRBPAC Meeting24 Safety Data Background Solicited injection site (local) AEs included: –Pain –Tenderness –Redness –Swelling

FDA VRBPAC Meeting25 Safety Data Background (cont) Solicited systemic AEs included: –Feverishness –Malaise –Body aches (exclusive of the injection site) –Nausea –Headache

FDA VRBPAC Meeting26 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)

FDA VRBPAC Meeting27 Local Reactogenicity Events Placebo N=48 7.5µg N= µg N= µg N=98 90 µg N=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 03.0%5.0%7.1%13.9% % Subjects with Severe (Gr 3) Injection Site AEs # of Injection Site AEs Pain22.5%21.9%33.5%35.1%36.1% Tenderness21.3%29.1%34.2%35.4%35.2% Erythema/Redness34.8%35.9%23.3%22.4%18.2% Induration/Swelling21.3%13.1%9.0%7.1%10.4%

FDA VRBPAC Meeting28 Systemic Reactogenicity Events Placebo N=48 7.5µg N= µg N= µg N=98 90 µg N=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 01.0%2.0%01.0% # of Systemic AEs Headache36%33.8%30.7%40.4%38.0% Malaise34.4%27.5%28.0%28.4%29.8% Body aches22.4%21.3%23.5%19.3%17.0% Nausea3.2%9.7%12.0%6.4%8.8% Feverishness4.0%7.7%5.7%5.5%6.4%

FDA VRBPAC Meeting29 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

FDA VRBPAC Meeting30 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

FDA VRBPAC Meeting31 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

FDA VRBPAC Meeting33 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.

FDA VRBPAC Meeting34 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.

FDA VRBPAC Meeting35 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.

FDA VRBPAC Meeting36 3. Please comment on studies to collect additional information about the effectiveness and safety following this vaccine’s use.

FDA VRBPAC Meeting37 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