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HEXAVAC ® A new liquid DTacP-IPV-Hib-HB hexavalent vaccine Overview of its clinical profile

HEXAVAC ® A new liquid DTacP-IPV-Hib-HB hexavalent vaccine Overview of its clinical profile. Benoît Soubeyrand M.D. (Courtesy L. Hessel). HEXAVAC ® : A NEW LIQUID DT a P-IPV-HIB - HB HEXAVALENT COMBINATION VACCINE. What is Hexavac ® ? Clinical development plan Safety profile

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HEXAVAC ® A new liquid DTacP-IPV-Hib-HB hexavalent vaccine Overview of its clinical profile

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  1. HEXAVAC® A new liquid DTacP-IPV-Hib-HBhexavalent vaccineOverview of its clinical profile Benoît Soubeyrand M.D. (Courtesy L. Hessel) B. Soubeyrand - VHPB October 2001 Malte

  2. HEXAVAC®:A NEW LIQUID DTaP-IPV-HIB-HB HEXAVALENT COMBINATION VACCINE • What is Hexavac® ? • Clinical development plan • Safety profile • Immunogenicity • Conclusions B. Soubeyrand - VHPB October 2001 Malte .

  3. WHAT IS HEXAVAC® (1): Composition and Presentation • A unique ready to use, preservative-free, liquid formulation, combining all 6 antigens in 0.5 ml • purified diphtheria toxoid, 20 IU (30 Lf) • purified tetanus toxoid, 40 IU (10 Lf) • adsorbed purified pertussis toxoid, 25 g • adsorbed purified FHA, 25  g • Polio type 1 (Mahoney strain), 40 D units • Polio type 2 (MEF 1 strain), 8 D units • Polio type 3 (Saukett strain), 32 D units • PRP-T, 12 g (PRP) • adsorbed, purified HBsAg, 5 g B. Soubeyrand - VHPB October 2001 Malte

  4. WHAT IS HEXAVAC® (2): Critical timelines • Start of the project Feb. 94 • 1st clinical lot available Jan. 95 • 1st inclusion phase 1 Feb. 95 • 1st inclusion phase 2 May 95 • 1st consistency batch (development scale) July 95 • 1st inclusion phase 3 June 96 • 1st consistency batch (industrial scale) Dec. 98 • 1st industrial lot April 99 • EMEA submission July 99 • CPMP positive opinion June 00 • Market autorisation Oct. 00 • Launch in Germany Oct. 00 i.e. - 5 years and 5 months: time to develop - 6 years and 8 months: time to register / market B. Soubeyrand - VHPB October 2001 Malte

  5. WHAT IS HEXAVAC® (3): Formulation Process • 200 different experimental formulations prepared, varying : • pH • ionic strength of different buffers (C032-, P043-) • batches of antigens • batches of adjuvant from different manufacturers • concentration of antigens • order of addition of antigens, adjuvant, buffer as well as conditions of blending • 50 different hexavalent formulations physico-chemically and immunologically tested • 7 optimized formulations extensively tested at 4°C, RT, 37°C • 2 semi-final formulations tested, over time, at + 4°C 1 final formulation for clinical development and industrial production B. Soubeyrand - VHPB October 2001 Malte

  6. HEXAVAC: Clinical development Plan (1) • Goals of clinical development : • To show that the hexavalent combination vaccine is safe and • induces protective immune responses equivalent (non-inferior) to previously licensed combination vaccinesPENTAVAC™ • and RECOMBIVAX® • To support clinically the consistency of manufacture by comparing the immunogenicity of three consecutively batches • To support the use of the vaccine with various vaccination • regimens:2, 3, 4/12-18 months or 2, 4, 6/12-18 months; • 3, 5 / 12 months B. Soubeyrand - VHPB October 2001 Malte

  7. HEXAVAC: Clinical development Plan (2) PHASE I Study PHASE II Study • Safety in toddler : France • HEXAVAC® : n=30 • Versus • DTaP-IPV-Hib/HB : n=28 • 14-18 months • Choice of formulation : France • HEXAVAC® : n=157 • Versus • DTaP-IPV-Hib/HB : n=155 • 2, 3, 4/12-14 months PHASE III Studies • Pivotal study – France (A) • HEXAVAC® : n=423 • PENTAVAC™ + RECOMBIVAX®n=425 • 2, 4, 6/12-18 months • Schedule study – France (D) • HEXAVAC® • 2, 3, 4/15-17 months : n=258 • Versus • 2, 4, 6/15-17 months : n=258 • Consistency lot study – Chile (B) • HEXAVAC® • 3 lots • 2, 4, 6 months : n=311 to 359 pergroup • Large scale safety – Germany (C) • HEXAVAC® • 2, 4, 6/12-14 months : n=1,783 • Schedule study – Sweden (E) • HEXAVAC® : n=180 • 3, 5, 12 months B. Soubeyrand - VHPB October 2001 Malte

  8. HEXAVAC: Clinical development Plan (3) • Safety of HEXAVAC® in children primed with DTwP-IPV-Hib (PENTACOQ®), France (F) • n = 1,304 • 2, 3, 4/16-20 months PHASE III studies : booster vaccination • Safety & Immunogenicity of HEXAVAC® in children primed with DTwP-IPV-Hib (PENTACOQ®) + RECOMBIVAX®, France (G) • n = 313 • 2, 3, 4/14-20 months • Safety & Immunogenicity of HEXAVAC® in children primed with DTaP-IPV-Hib (PENTAVACTM) + RECOMBIVAX®, Turkey (H) • n = 129 • 2, 3, 4/14-18 months B. Soubeyrand - VHPB October 2001 Malte .

  9. HEXAVAC: Clinical development Plan (4) • Database submitted in the application file to CPMP • 11507 doses of vaccines administered to 3 905 infants in primary series. • 4 437 booster doses given to toddlers primed with either whole-cell or acellular Pertussis combination vaccines: • - Pentacoq™ ( DTwP-IPV//PRP-T) • - Pentavac™ ( DTaP-IPV//PRP-T) • European license received on October 24th 2000 B. Soubeyrand - VHPB October 2001 Malte

  10. HEXAVAC® :Safety profile (1) In all studies, evaluation of safety included: • Immediate reactions within the first 30 minutes after each dose • Local reactions and systemic events from 30 minutes to 72 hours following each dose • Any adverse event that resulted in a visit to a physician 4 and 30 days after each injection • Any serious adverse event (SAE) occurring throughout the trial. B. Soubeyrand - VHPB October 2001 Malte

  11. 25 20.3 HEXAVAC® PENTAVACTM RECOMBIVAX® 20 15.8 14.5 13.8 15 12.1 % of Infants 10 6.8 3.8 5 3.3 1.5 0 Swelling  2 cm Redness  2cm Any reaction HEXAVAC® :Safety profile (2) Local reactions(%) followingprimary seriesin infants receiving HEXAVAC® (N = 423) or PENTAVACTM + RECOMBIVAX® (N = 425) B. Soubeyrand - VHPB October 2001 Malte

  12. HEXAVAC® PENTAVACTM RECOMBIVAX® HEXAVAC® :Safety profile (2) Local reactions(%) within 3 days of aboosterdose (12-18 months) of HEXAVAC® (n=400) or PENTAVACTM + RECOMBIVAX® (n=402) 35 28.7 30 26.9 24.4 25 20.9 20.7 19.9 20 % of infants 15 10.2 10 8.0 8.0 5 0 Anyreaction Swelling 2cm Redness 2cm B. Soubeyrand - VHPB October 2001 Malte

  13. HEXAVAC® PENTAVACTM +RECOMBIVAX® HEXAVAC® :Safety profile (3) Systemic reactions(%) followingprimary seriesin infants receiving HEXAVAC® (N = 402-423) or PENTAVACTM + RECOMBIVAX® (N = 425) 60 50 45.7 42.2 40 26.9 30 % of infants 23.7 14.7 20 14.5 11.3 9.9 10 0 Any event Fever 38°C drowsiness Irritability Mallet E. et al. Pediatr Infect Dis J, 2000; 19:1119-27 B. Soubeyrand - VHPB October 2001 Malte

  14. HEXAVAC® PENTAVACTM +RECOMBIVAX® Any event Fever38°C Drowsiness Irritability HEXAVAC® :Safety profile (4) Systemic reactions(%) within 3 days of aboosterdose (12-18 months) of HEXAVAC® (n=400) or PENTAVACTM + RECOMBIVAX® (n=402) Systemicadverse events 47.6 50 40.5 40 32.4 29.4 30 % of infants 20.0 18.2 20 10 7.0 3.7 0 Mallet E. et al. B. Soubeyrand - VHPB October 2001 Malte

  15. HEXAVAC® :Safety profile (5), summary Local and systemic reactions (%) within 3 days following primary series in infants and booster in children primed with Hexavac® B. Soubeyrand - VHPB October 2001 Malte

  16. HEXAVAC®:Immunogenicity (1) * Response measured by EIA B. Soubeyrand - VHPB October 2001 Malte

  17. 100 99.7 100 100 100 100 100 99.7 96.6 93.7 93.7 100 91.8 90.5 88.6 80 HEXAVAC® 60 (n = 305-331) PENTAVACTM+RECOMBIVAX® 40 (n = 301-332) 20 0 HBsAg PRP PT FHA Tetanus Diphtheria Poliovirus 10 mIU/ml 0.15 4- fold 4- fold 0.01 0.01 5 µg/ml increase (1/dil) increase IU/ml IU/ml HEXAVAC®:Immunogenicity (2) Comparison of Seroprotection / Seroconversion rates between Hexavac®and PentavacTM + Recombivax® 1 month aftertheprimary series (2, 4, 6 months) Seroprotection rate (%) Seroprotective titres Mallet E. et al. Pediatr Infect Dis J 2000; 19 : 1119-27 B. Soubeyrand - VHPB October 2001 Malte

  18. PentavacTM + Recombivax® Hexavac® HEXAVAC®:Immunogenicity (3) Post-dose 3, pre- and post-booster antibody results (GMTs) T FHA D PT Polio 2 Polio 3 Polio 1 Mallet E. et al. Pediatr Infect Dis J 2000; 19 : 1119-27 B. Soubeyrand - VHPB October 2001 Malte

  19. PentavacTM + Recombivax® Hexavac® HEXAVAC®:Immunogenicity (4) Post- dose 3, pre-booster and post-booster anti-HBs antibody responses: GMTs (% seroprotection rates) 10000 3026 (100) HBs 983 (100) 1000 932 (96.6) 434 (96.6) HBs antibody (mIU/ml) 332 (98.4) 100 47.3 (81.7) 10 post dose 3 pre-booster post-booster Mallet E. et al. Pediatr Infect Dis J 2000; 19 : 1119-27 B. Soubeyrand - VHPB October 2001 Malte

  20. HEXAVAC® : Protection against Hepatitis B anti HBs (mIU /ml) after primo-immunisation with various vaccines B. Soubeyrand - VHPB October 2001 Malte

  21. PentavacTM + Recombivax® Hexavac® post dose 3 pre-booster post-booster HEXAVAC®:Immunogenicity (5) Post dose 3, pre-booster and post-booster anti-PRP antibody responses: GMTs (%seroprotection rates) 100 23.0 (100) 16.7 (100) 10 Hib 3.69 (99.7) 2.06 (93.7) Anti-PRP antibody (µg/ml) 0.6 (91.4) 1 0.4 (77.5) 0,1 0,01 Mallet E. et al. Pediatr Infect Dis J 2000; 19 : 1119-27 B. Soubeyrand - VHPB October 2001 Malte

  22. HEXAVAC®:Protection against Hib GMC after primary immunisation in the first 6 months of life 100 10 1 0.1 PentavacⓇ HexavacⓇ Anti-PRP titres (µg/ml) HbOC PRP-D PRP-OMP PRP-T PRP-T separate PRP-T mixed Eskola J. Lancet 1999; 354 : 2063 B. Soubeyrand - VHPB October 2001 Malte

  23.  0.15  5 4- fold  4- fold  0.01  0.01 (1/dil) increase µg/ml increase IU/ml IU/ml HEXAVAC®:Immunogenicity (6) Seroprotection / seroconversion rates one month following the administration of HEXAVAC® at 2, 4, 6, or 2, 3, 4, months of age Seroprotective titres 10 mIU/ml Camier P. et al. ESPID 2000 B. Soubeyrand - VHPB October 2001 Malte

  24. Seroprotective titres 10 mIU/ml • 0.10 IU/ml • 0.10 IU/ml • 5 • (1/dil) • 1.0 µg/ml • 4- fold increase • 4- fold increase HEXAVAC®:Immunogenicity (7) Seroprotection / seroconversion rates one month following the booster dose of HEXAVAC® given at 2, 3, 4 / 15-17, or 2, 4, 6 / 15-17 or 3, 5 / 12 months of age Camier P. et al : ESPID 2000; Flodmark CE et al : PIDS 2001 B. Soubeyrand - VHPB October 2001 Malte

  25. CONCLUSIONS • Hexavac®, the liquid combined hexavalent vaccine: • is well tolerated • provides protection and seroconversion in the range of other licensed vaccines containing aP • immune responses to PRP and HBs are in the range of those reported with vaccines proven to be efficacious • confers excellent priming for all antigens as evidenced by strong booster responses B. Soubeyrand - VHPB October 2001 Malte

  26. Aventis Pasteur Merck & Co. AventisPasteur MSD A. Hoffenbach P. Mendelman G. Chryssomalis E. Pines J. Boslego M. Garnier L. Hessel P. Fabre F. Schödel E. Vidor H. Matthews T. Staub H. Salomon M. Dupuy C. Blondeau • HEXAVAC®:Clinical development team • Investigators : E. Mallet, J. Lang, P. Camier, P. Reinert, F. Undreiner, F. Roussel, R. Lagos, M. LevineB. Belohradsky, J. Liese, S. Stojanov, G. Kanra, P. Carriere, M. Girard, M. Muller and all participating pediatricians • Hexavac project team • And all participating babies andparents B. Soubeyrand - VHPB October 2001 Malte

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