Rotarix : Global Efficacy against Severe RV GE due to G1 and non-g1 (G2, G3, G4, G9) RV Types

Rotarix : Global Efficacy against Severe RV GE due to G1 and non-g1 (G2, G3, G4, G9) RV Types 8 th International Rotavirus Symposium Istanbul, 3 rd June 2008 Dr. Norman Begg, Vice President, Clinical Development GlaxoSmithKline Biologicals, Rixensart, Belgium

Challenges for the development of a global Rotavirus vaccine No increased risk of IS compared to placebo Broad protection against known and emerging strains Efficacy from an early age and peak incidence period No interference with co-administered antigens Ease of inclusion in immunisation schedules Efficacy in developing and developed countries

Percent Efficacy 100 90 80 70 60 50 40 30 20 10 0 Rational for Vaccination with Human RV Strain Natural RV infection attenuates severity of subsequent infections, regardless of serotype 1-3 87 100 73 75 38 One Previous RV infection moderate to severe diarrhea mild diarrhea asymptomatic infection 62 Two Previous RV infections 1 Velazquez et al, N Eng J Med 1996 335 1022 1028 ; 2 Bernstein DI, et al. JID. 1991; 164(2); 277-83 ; 3 Velazquez et al, J Infect Dis 2000 182 1602 1609

Human RV Vaccine - Rotarix Lyopholized vaccine + liquid diluent (CaCO 3 ) 1 ml per dose Each dose: 10 6 CCID 50 of live, attenuated HRV strain G1 P(8) Orally administered 2 doses 1 st dose beginning at 6 weeks of age 2 nd dose at 4 weeks after first dose; completed by 24 weeks of age GlaxoSmithKline Biologicals, Rotarix TM Summary of Product Characteristics (Dec. 2007)

Pivotal phase III studies in Latin America and Europe Ruiz-Palacios et al. for the Human Rotavirus Vaccine Study Group. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354: 11 22. Vesikari et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet 2007; 370: 1757 63. 5

No increased risk of Intussusception Vaccine group Placebo group Safety cohort N=31,673 Safety cohort N=31,552 Cases of IS 0 31 days 6 7 0 100 days Relative Risk = 0.85 (0.30 ; 2.42)* 9 16 Relative Risk = 0.56 (0.25 ; 1.24)* No increased risk for IS compared to placebo Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354: 11-22 ; Macias M. et al., abstract, ICAAC, 2005, Washington, USA (poster) *95% CI

Latin America: Type-specific Efficacy for Severe Rotavirus GE From 2 weeks post-dose 2 until 24 months of age (ATP cohort) Vaccine efficacy (%) 100 90 80 70 60 50 40 30 20 10 0 * Not statistically significant G1P[8] G2P[4] G3P[8] G4P[8] G9P[8] Low Number of G2P[4] due to low circulation of strain type Linhares, A.C., et al. Lancet 2008 Apr 5;371(9619):1181-9 82% [65;92] 79% [25;96] 39%* [<0;84] 62% [4;87] 87% [73;94]

Europe: Type-specific Efficacy for Severe Rotavirus GE From 2 weeks post-dose 2 until end of the 2 nd RV season (ATP cohort) Vaccine efficacy (%) 100 90 80 70 60 50 40 30 20 10 0 96% [90;99] 86% [24;99] 94% [53;100] 95% [68;100] 85% [72;93] G1P[8] G2P[4] G3P[8] G4P[8] G9P[8] Vesikari T, et al. Lancet 2007 Nov 24;370(9601):1757-63.

Latin America: Efficacy over peak incidence (2 years) From 2 weeks post-dose 2 until 12 months of age From 2 weeks post-dose 2 until 24 months of age Vaccine efficacy (%) 100 90 80 70 60 50 40 30 20 10 0 85% [71;93] 81% [71;87] Severe RV GE Vesikari 85% [70;94] RV GE hosp. 83% [73;90] Severe RV GE Vesikari RV GE Hospitalization 40% [29;53] 39% [29;48] All causes Severe GE All-cause Severe GE Linhares AC, et al. Lancet 2008 Apr 5;371(9619):1181-9

Europe: Efficacy lasting 2 seasons From 2 weeks post-dose 2 until end of the 1st RV season (ATP cohort) From 2 weeks post-dose 2 until end of the 2nd RV season (ATP cohort) Vaccine efficacy (%) 100 90 80 70 60 50 40 30 20 10 0 87% [80;92] 79% [73;84] 96% [90;99] 90% [85;94] 100% 96% [82;100] [84;100] 92% [84;96] 84% [77;89] Any RV GE Severe RV GE RV GE Hosp Medicallyattended RV GE Vesikari T, et al. Lancet 2007 Nov 24;370(9601):1757-63. 75% [46;89] 72% [53;83] All-cause GE Hosp

Europe: Efficacy after one dose From Dose 1 up to before Dose 2 (Total Vaccinated Cohort) Vaccine efficiacy (%) 100 90 80 70 60 50 40 30 20 10 0 90% [9;100] Any RV GE 100% [-23;100] Severe RV GE Vesikari T, et al. Lancet 2007 Nov 24;370(9601):1757-63 ; GlaxoSmithKline Biologicals, Rotarix Summary of Product Characteristics (Dec 2007) According to Rotarix Summary of Product characteristics 2 doses are indicated.

Co-administration with other vaccines DTPw, DTPa, HBV, Hib, IPV, OPV, Men C, PCV-7 High Rotarix immune responses maintained No impairment of immune responses to any co-administered vaccine antigens Vesikari et al. PIDJ 2004,23:937-43 Salinas B et al. PIDJ, 2005 24/9:807-815 Phua K et al. JID, 2005;192(suppl 1): S6-S16 Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354: 11-22 Tejedor JC et al. ESPID, Basel, Switzerland May 3 5, 2006, Abstract 456, Schuster VT et al. ESPID, Basel, Switzerland May 3 5, 2006, Abstract 461

Latin America (Rota 024): Co-administration of Rotarix with Oral Polio Vaccine Infants of 6-12 weeks 100 90 82% [54;93] 88% [64;97] Co-administration: OPV + 2 doses RIX4414 or Placebo (n=4376) (n=2192) Vaccine efficacy (%) 80 70 60 50 40 30 20 Efficacy follow-up: 7.4m 10 0 Severe RV GE RV GE Hospitalization No impact on the efficacy of Rotarix In line with the high efficacy against severe RVGE of 85% demonstrated in the Latin American study with staggered OPV co-administration Tregnaghi, M. et al., Abstract, 13th ICID Kuala Lumpur, Malaysia- June 19-22, 2008 http://www.x-cd.com/isid08/prof3674.html

Ease of inclusion in immunisation schedules Oral presentation 2 doses Flexible schedule starting from 6 weeks of age No interference with currently co-administered vaccines Rotarix can be flexibly integrated into a variety childhood immunisation schedules: 6,10 weeks; 6,14 weeks; 10,14 weeks; 2, 3 months; 2, 4 months; 3, 4 months or 3, 5 months of age Vesikari et al. PIDJ 2004,23:937-43 Salinas B et al. PIDJ, 2005 24/9:807-815 Phua K et al. JID, 2005;192(suppl 1): S6-S16 Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354: 11-22 Tejedor JC et al. ESPID, Basel, Switzerland May 3 5, 2006, Abstract 456, Schuster VT et al. ESPID, Basel, Switzerland May 3 5, 2006, Abstract 461

Variance in serotype distribution G4P[8] 3.4% G9P[8] 17.2% G3P[8] 12.1% GXP[6] 1.7% Unknown 3.4% Latin America G1P[8] 51.7% 1 st Year Europe G9P[8] 33.9% G1P[8]+G4P[8] 0.8% G1P[8] 41.5% G2P[4] 12.1% G4P[8] 12.7% G3P[8] 5.1% G2P[4] 5.9% G9P[8] 54.4% G3P[6] 1.0% G1P[8] 24.3% G4P[8] 15.6% G2P[4] 1.0% G3P[8] 5.8% 2 nd Year Mixed 2.3% G12P[8] 1.2% G9P[8] 39.2% G4P[8] 4.7% Linhares AC, et al. Lancet 2008 Apr 5;371(9619):1181-9 ; Vesikari T, et al. Lancet 2007 Nov 24;370(9601):1757-63 Unknown 4.1% G3P[8] 4.1% G1P[8] 31.6% G2P[4] 12.9%

Efficacy in all Regions Rota-023 (11 countries) Severe RV GE 1 year 85% (71-93) 2 years 81% (71-87) Hospitalization for RV GE 1 year 85% (70-94) 2 years 83% (73-90) Linhares AC, et al. Lancet 2008 Apr 5;371(9619):1181-9 Rota-036 (6 countries) Severe RV GE1 season 96% (90-99) 2 seasons 90% (85-94) Hospitalization for RV GE 1 season 100% (82-100) 2 seasons 96.0% (84-100) Any RV GE 1 season 87% (80-92) 2 seasons 79% (73-84) Vesikari T, et al. Lancet 2007 Nov 24;370(9601):1757-63. Rota-024 OPV co-ad (6 countries) Severe RV GE 1st year 82% (54-93) Hospitalization for RV GE 1st year 88% (64-97) Lopez, P. et al., Abstract, 13th ICID Kuala Lumpur, Malaysia- June 19-22, 2008 http://www.x-cd.com/isid08/prof4729.html Rota-028/029/030 (3 countries) Severe RV GE 1 year 100% (72-100) 2 years 96% (86-100) Hospitalization for RV GE 1 year 100% (67-100) 2 years 94% (81-99) Phua, K.B. et al., Abstract, 13th ICID Kuala Lumpur, Malaysia- June 19-22, 2008 http://www.x-cd.com/isid08/prof3718.html Rota-037 Interim analysis to be presented at 8 th International RV symposium Madhi, S., Oral presentation, 8th international Rotavirus Symposium, Istambul, Turkey, June 3-4, 2008 http://www.rotavirus2008.com

Summary: Rotarix No increased risk of IS compared to placebo Broad protection against known and emerging strains Efficacy from an early age, lasting 2 years No interference with co-administered antigens Ease of inclusion in immunisation schedules Efficacy in developing and developed countries