A Human Rotavirus Vaccine Dr. Batrice De Vos GlaxoSmithKline - PowerPoint PPT Presentation

7th International Rotavirus Symposium Lisbon, Portugal, 12-13 June 2006 A Human Rotavirus Vaccine Dr. Béatrice De Vos GlaxoSmithKline Biologicals Rixensart, Belgium Rotarix is a trade mark of the GlaxoSmithKline group of companies

1 Rotarix™ - rotavirus vaccine Biography of a Human Attenuated RV Vaccine Rix4414 89-12 strain isolated from stools of a 15-month old boy in Cincinnati Passaged in Primary African J Gamble Inst. Med. Green Monkey Kidney (AGMK) Research, Cincinnati Further Passaged in AVANT Immunotherapeutics AGMK Further Passaged in Vero Cell Line GSK Bio & Cloning steps Further passaged RIX4414 in Vero cell line master seed Rotarix ™ vaccine lot

2 Rotarix™ - rotavirus vaccine Why was HRV strain 89-12 a good vaccine candidate? • 1989 : Natural infection with 89-12 G1 RV strain from Cincinnati provided excellent protection against RV disease during next RV season • Live vaccine was prepared by serial passage of 89-12 strain • 1997-98 : Placebo controlled study reported a VE against “any” RV GE of 89% and 100% against “very severe” RVGE • 1998-99 : F/U showed protection in a 2nd year of 100% against “very severe” RVGE Ward et al , J. Infect. Dis. 1991,164: 277-283; Bernstein D et al , 1999. Lancet 354:287-290 Bernstein D, et al , 2000. Abstract IDSA 2000

3 Rotarix™ - rotavirus vaccine Vaccine Profile • Live, attenuated, human RV (parent strain 89-12) 1 • G1P[8] 2 • Broad cross-protection 2,3 • Oral, 1mL • Two doses from 6 weeks of age, minimum 4 weeks apart 4 • Storage at 2–8°C 4 • Co-administration with other vaccines: DTPw, DTPa, HBV, Hib, IPV, OPV 4 , Men C 5 , Strep pneum 6 1 Bernstein et al, Lancet 1999 354 287–290; 2 Offit, Sem Pediatr Infect Dis 2002 13 190–195; 3 Ruiz-Palacios et al, WSPID 2002 4 Rotarix ™ Prescribing Information 5 Tejedor JC T et al. ESPID, Basel, Switzerland May 3-5, 2006 Abstract 456 6 Schuster V T et al. ESPID, Basel, Switzerland May 3-5, 2006 Abstract 461

4 Rotarix™ - rotavirus vaccine Phase I – II – III Studies Belgium Canada Germany Czech Finland Singapore Republic USA France Bangladesh Spain Hong Kong Italy Taiwan Thailand Vietnam India Mexico Korea Panama Costa Rica Venezuela Colombia Brazil Peru Honduras Chile Nicaragua South Africa Argentina Dominican Rep. Malawi … a worldwide development

5 Rotarix™ - rotavirus vaccine Phase III Efficacy and Safety Study 023 Latin-America & Finland

6 Pivotal Phase III Study 023 Phase III study in Latin America (023) Trial profile n=31,673 RIX4414 2 nd Dose 1 st Dose n=63,225 infants of 6-13 weeks of age enrolled and randomized (1:1) n=31,552 Placebo month 0 Month 1-2 Month 2-4 Month 9-10 Safety analysis 1yr Efficacy (N=63,225) analysis (N=17,867) Routine immunizations were co-administered according to local regulations Study conducted in 4Q 2003-2005 (2yr) Ruiz-Palacios G. et al N. Engl. J. Med. 2006; 354: 11-22

7 Pivotal Phase III Study 023 Safety cohort (N=63,225) 18 sites in 12 countries Dominican Republic Mexico 4056 (6.4%) 13245 (20.9%) Panama 4061 (6.4%) Honduras 4195 (6.6%) Venezuela 4250 (6.7%) Nicaragua 4057 (6.4%) Brazil Colombia 3218 (5.1%) 3910 (6.2%) Peru 12044 (19.0%) Argentina 4671 (7.4%) Chile Finland 3458 (5.5%) 2060 (3.3%) Ruiz-Palacios G. et al N. Engl. J. Med. 2006; 354: 11-22

8 Pivotal Phase III Study 023 – Safety Methods Placebo-controlled, randomized, double blind study (N=63,225) • Study population 31.673 vaccinees and 31.552 placebo recipients • Dose 1: mean age 8.2 weeks (97% ≤ 13 weeks old) • Dose 2: mean age 15.8 weeks • Case Definition Definite IS according to Brighton Collaboration Group • Demonstration at surgery • Gas or liquid contrast enema • Abdominal ultrasound with specific characteristic features proven to be reduced by hydrostatic enema • Autopsy criteria Ruiz-Palacios G. et al N. Engl. J. Med. 2006; 354: 11-22

9 Pivotal Phase III Study 023 – Safety Occurrence of Definite IS Cases Compared to RotaShield ™ -Associated Cases 1 20 Dose 1 RIX4414/placebo RotaShield™ 15 10 IS cases V V P P P P P P P V 5 0 75 83 0 10 20 30 40 50 60 70 20 Dose 2 15 V 10 IS cases V V V V P P P P P P V P P P 5 V = Vaccine 0 P = Placebo 107 145 0 10 20 30 40 50 60 70 1 Murphy TV et al , N Engl J Med, 2001. Vesikari T et al . ESPID 2005, abstract 31

10 10 Pivotal Phase III Study 023 – Safety Safety - Intussusception Surveillance Vaccine group Placebo group Safety cohort N=31,673 Safety cohort N=31,552 Efficacy cohort Efficacy cohort N=10,159 N=10,010 Cases of IS 6 7 0 � 31 days 6 7 Relative Risk = 0.85 (0.30 ; 2.42) 9 1 16 10 0 � 100 days 9 1 16 10 Relative Risk = 0.56 (0.25 ; 1.24) Relative Risk = 0.1 (0.02 ; 0.60) 0 � 1 year 4 14 4 14 Relative Risk = 0.28 (0.1 ; 0.81) Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354: 11-22 Macias, abstract, ICAAC, 2005, Washington, USA (poster)

11 11 Phase III Study 036 Study 023 – Latin America Results : 1yr Efficacy

12 12 Pivotal Phase III Study 023 – Efficacy Vaccine efficacy against severe RV GE From 2 weeks post-dose 2 to 1 year of age N subjects with severe RV GE Vaccinees Placebo Vaccine efficacy (95% CI) P-value n=9,009 n=8,858 84.7 Clinical 12 77 < 0.001 (71.7 - 92.4) Vesikari 84.8 11 71 < 0.001 score ≥ 11 (71.1 – 92.7) ATP efficacy cohort Ruiz-Palacios G. et al N. Engl. J. Med. 2006; 354: 11-22

13 13 Pivotal Phase III Study 023 – Efficacy Vaccine efficacy against RV GE hospitalization From 2 weeks post-dose 2 to 1 year of age N subjects hospitalized Vaccinees Placebo Vaccine efficacy [95% CI] P-value n=9,009 n=8,858 85 Clinical 9 59 < 0.001 (69.6 - 93.5) Vaccine Efficacy against any GE hospitalization 42% (95% CI 29-53) Ruiz-Palacios G. et al N. Engl. J. Med. 2006; 354: 11-22

14 14 Pivotal Phase III Study 023 – Efficacy Efficacy against severe RV GE by main serotype From 2 weeks post-dose 2 to 1 year of age (95% CI) ATP efficacy cohort 91.8 90.8 87.3 86.9 (74.1 - 98.4) (70.5 - 98.2) (64.1 - 96.7) 100 (62.8 - 96.6) 90 Clinical 80 Vaccine efficacy (%) 70 Vesikari scale 45.4 (-81.5 - 85.6) 60 41.0 50 (-79.2 - 82.4) 40 30 20 10 0 G1P[8] G3P[8], G4P[8], G9P[8] G2P[4]* * In a meta-analysis including the results of 023 and 2 phase II studies, the efficacy of RIX4414 against the G2P[4] type was 67% (CI 95%: 15 - 87%) Ruiz-Palacios G. et al N. Engl. J. Med. 2006; 354: 11-22

15 15 Effect On Co-administered Vaccines Sero-positivity / protection rate of DTPw-HBV/Hib and OPV separately (post dose 2 ) 100 90 RIX4414 80 n 70 Placebo o i s 60 r e 50 v n o 40 c - 30 o r e 20 s % 10 0 D T Pertussis HBV Hib (PRP) Polio 1 Polio 2 Polio 3 1 1 2 3 4 5 5 5 1 ELISA, cut off at 0.1UI/mL 2 ELISA, cut off at 15 EL.U/mL 3 AUSAB, Abbott Laboratories cut off at 10mIU/mL 4 ELISA, cut off at 0.15 µg/mL 5 Virus microneutralization cut off titer ≥ 8 Salinas B. et al, Pediatr Infect Dis J 2005, 24(9):807-816

16 16 Effect On Polio 1, 2 & 3 Seroprotection After D3 100 RIX4414 + IPV RIX4414 + OPV • Percentage of infants 95 Placebo + OPV 90 85 80 Polio 1 Polio 2 Polio 3 Polio 1 Polio 2 Polio 3 Polio 1 Polio 2 Polio 3 Study 014 Study 013 Study 024 (ATP cohort) Virus microneutralization cut off titer ≥ 8

17 17 Rotarix™ - rotavirus vaccine Phase III Efficacy Study 036 Europe

18 18 Phase III Study 036 Phase III Study in Europe (036) Trial profile n=2,646 RIX4414 n=3,994 2 nd dose 1 st dose infants enrolled and randomised (2:1) n=1,348 Placebo Month 0 Months 1–2 Months 7-9 Months 19-21 Age 6-14 Age 10–24 Age 10-11 Age 22-23 weeks weeks months months Season 1 efficacy Season 2 efficacy analysis analysis Co-administered with routine childhood vaccinations Study conducted 4Q 2004 – 2005 (Yr 1) Vesikari T et al. ESPID, Basel, Switzerland May 3–5, 2006, Abstract 75

19 19 Phase III Study 036 - Objectives 124 sites in 6 EU countries ~4000 infants 74% 7% 7,5% 3,7% 0,6% 7,5%

20 20 Phase III Study 036 Study Design • Randomized, double-blind, placebo-controlled study in 6 European countries • 2646 vaccinees • 1348 placebo recipients • Dose 1: 5-18 weeks of age (mean: 11.5 wks) • Dose 2: 10-30 weeks of age (mean: 19.6 wks) • Co-administration with routine childhood vaccines • Surveillance period: 6 months, until end of the 1st RV season after vaccination (second year ongoing) • ~ 90% of infants not vaccinated before RV season • Peak incidence of RVGE April - May 2005 Vesikari T et al. ESPID, Basel, Switzerland May 3–5, 2006, Abstract 75

21 21 Phase III Study 036 Methods • Gastroenteritis : Diarrhea with or without vomiting Severe GE : Score ≥ 11 on 20-point Vesikari scale 1 • GE Stools analyzed for RV by ELISA ( RotaClone TM ). RV • positive samples tested by RT-PCR followed by Reverse Hybridization assay to determine G and P types • Primary analysis on ATP cohort including 2572 vaccinees and 1302 placebo recipients 1 Ruuska and Vesikari, Scand J Infect Dis, 1990