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GlaxoSmithKline’s Human Rotavirus Vaccine ROTARIX ®

GlaxoSmithKline’s Human Rotavirus Vaccine ROTARIX ®. Vaccines and Related Biological Products Advisory Committee February 20, 2008. GlaxoSmithKline Presentation. Clare Kahn, Ph.D Vice President North America, Regulatory Affairs. Introduction. Leonard Friedland, M.D.

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GlaxoSmithKline’s Human Rotavirus Vaccine ROTARIX ®

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  1. GlaxoSmithKline’s Human Rotavirus VaccineROTARIX® Vaccines and Related Biological Products Advisory Committee February 20, 2008

  2. GlaxoSmithKline Presentation Clare Kahn, Ph.DVice President North America, Regulatory Affairs Introduction Leonard Friedland, M.D. Executive Director - Clinical R&DNorth America, Vaccines Clinical Development Plan Clinical Trial Results Thomas Verstraeten, M.D. Director Head Worldwide Safety, Vaccines Post-marketing Safety Data Pharmacovigilance Plan Clare Kahn, Ph.D Conclusion

  3. Proposed Names Proprietary Name Rotavirus Vaccine, Live, Oral Trade NameRotarix®

  4. Human RV Vaccine - Rotarix • Lyophilized vaccine + liquid diluent (CaCO3) • 1 mL per dose • Each dose: ≥106 CCID50 of live, attenuated HRV strain • Orally administered • 2 doses • 1st dose beginning at 6 weeks of age • 2nd dose at ≥4 weeks after first dose; completed by 24 weeks of age

  5. Proposed Indication ROTARIX is indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (including G2, G3, G4 and G9) when administered as a 2-dose series to infants 6 to 24 weeks of age.

  6. 610,000 1 : 205 2.4 million 1 : 50 24 million 1 : 5 114 million 1 : 1 Estimated Global Prevalence of Rotavirus Disease Annual Burden Risk by 5th Birthday Deaths Hospitalizations Outpatient Visits RV Episodes Glass RI, et al. Lancet 2006;368:323-332

  7. Annual Burden Risk by 5th Birthday 20-60 1 : 100,000 Deaths 55,000-70,000 Hospitalizations 1 : 80 Outpatient Visits 600,000 1 : 7 2.7 million 4 : 5 RV Episodes Glass RI, et al. Lancet 2006;368:323-332 Estimated US Prevalence of Rotavirus Disease

  8. Distribution of Rotavirus Strains by Region between 1973 and 2003 Latin America (n=2,950) North America (n=2,892) Europe (n=17,475) n= number of RV infections analyzed Santos et al. Rev Med Virol 2005;15:29-56

  9. Rotavirus Virion • 11 segments of dsRNA encased by 3 protein capsids • VP6 common to all RV strains • Outer capsid proteins VP7 (G protein) and VP4 (P protein) induce neutralizing antibodies involved in disease protection • Human RV classified into 10 G (VP7) and 11 P (VP4) types • 5 G-P combinations constitute 90% of worldwide strains:G1P[8], G2P[4], G3P[8], G4P[8], G9P[8] • P[4] and P[8] share cross-reactive epitopes Figure adapted from Cunliffe et al, Lancet 2002;359:640–642

  10. Human RV Vaccine - Rotarix Human rotavirus strain circulating in Cincinnati in 1989 33 passages in cell culture G1P[8] Initial Safety and Efficacy studies1 Limiting dilution cloning in Vero cells and further passage in tissue culture Live-Attenuated Human Rotavirus Vaccine (RIX4414 - Rotarix®) 1Bernstein et al, Lancet, 1999; 354:287-290 G1P[8]

  11. Basis for Vaccination with Human Strain Natural RV infection attenuates severity of subsequent infections, regardless of serotype1-3 One Previous RV infection 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

  12. Rotavirus Vaccines - History • Development of live attenuated rotavirus vaccines derived from animal hosts began in 1970s • RotaShield®:rhesus-human reassortant vaccine licensed in the US in 1998 • Withdrawn in 1999 due to causal link with intussusception • RotaTeq®: human-bovine reassortant vaccine licensed in 2006 • Rotarix®: live attenuated human RV vaccine Large scale placebo-controlled safety trials required to refute intussusception related to vaccination

  13. Global Strategy for Rotarix Vaccine Development Following RotaShield withdrawal in 1999: • Need for very large studies to assess risk of possible vaccine-induced intussusception (60,000 subjects) • WHO recommendation to manufacturers to extend their development programs to countries with high medical need • Majority of deaths resulting from RV gastroenteritis occur in South East Asia, Africa and Latin America • Other considerations:- Availability of sound epidemiology data on RV disease and intussusceptions rates- a healthcare infrastructure to conduct very large trials

  14. CanadaUSA Finland France Germany Spain Czech Rep Italy Mexico Honduras Nicaragua Panama Dominican Rep. Thailand Singapore Brazil Venezuela Colombia Peru Chile Argentina South Africa Phase III – Study 023 Phase III – Study 036 Other BLA Studies Rotarix BLA Development

  15. Global Clinical Development Non US clinical studies were pivotal for US licensure as all complied with the following criteria defined by FDA for acceptance of foreign clinical data (21 CFR §312.120, § 314.106; ICH E5) • Circulating serotypes and IS background rates are similar to the US • Objectivity of pivotal endpoints • Identification of IS • Case definition for RV GE • Use of internationally accepted and widely used scoring system for severity of GE • Study design and conduct in compliance with GCPs

  16. EU Canada Norway Iceland Kazakhstan Switzerland Bangladesh Hong Kong Macau Malaysia Myanmar Philippines Singapore Sri Lanka Taiwan Thailand Vietnam Argentina Aruba Bolivia Brazil Chile Colombia Costa Rica Curacao Dom Republic Ecuador El Salvador Guatemala Honduras Jamaica Mexico Nicaragua Panama Paraguay Peru Suriname Trinidad Venezuela Bahrain Israel Jordan Kuwait Morocco Oman Pakistan Qatar Saudi Turkey UAE Yemen Australia New Zealand Angola Benin Burkina Faso Cameroon Congo DRC Egypt Gabon Guinea Ivory Coast Kenya Madagascar Malawi Mali Mauritania Mauritius Mozambique Namibia Niger Nigeria RCA Senegal South Africa Togo Registration Status for Rotarix • WHO prequalification – Feb 2007 • 12 million doses distributed

  17. GlaxoSmithKline Presentation Clare Kahn, Ph.D.Vice PresidentNorth America Regulatory Affairs Introduction Leonard Friedland, M.D. Executive Director - Clinical R&DNorth America, Vaccines Clinical Development Plan Clinical Trial Results Thomas Verstraeten, M.D. DirectorHead, Worldwide Safety, Vaccines Post-marketing Safety Data Pharmacovigilance Plan Clare Kahn, Ph.D. Conclusion

  18. Total Exposure = 75029 subjects Total Exposure = 75029 subjects Rotarix<106.0 CCID50 n = 3076 Rotarix>106.0 CCID50 n = 37214 Rotarix<106.0 CCID50 n = 3076 Rotarix>106.0 CCID50 n = 37214 Placebo n =34739 Placebo n =34739 Phase III Phase II Phase II Phase III Efficacy, Safety (IS), Immuno Efficacy, Safety,Immuno Safety, Immuno Efficacy, Safety (IS), Immuno Immuno, Safety Efficacy, Safety,Immuno Safety, Immuno Immuno, Safety Study 005 US, Canada n=212 n=209n=108 Study 005 US, Canada n=212 n=209n=108 Study 004 Finland n=270 n=135 Study 023 Latin America, Finland n=31673n=31552 Study 039 Thailand n=174 n=52 Study 004 Finland n=270 n=135 Study 023 Latin America, Finland n=31673n=31552 Study 039 Thailand n=174 n=52 Lot consistency,Safety, Immuno Immuno US coadvaccines, Safety Efficacy, Safety,Immuno Immuno OPV Coad, Safety Immuno US coadvaccines, Safety Efficacy, Safety,Immuno Immuno OPV Coad, Safety Lot consistency,Safety, Immuno Study 060 US n=459 Study 014S. Africa n=297 n=150 Study 006 Latin America n = 1139 n=570n=567 Study 014S. Africa n=297 n=150 Study 033 Latin America n=730n=124 Study 006 Latin America n = 1139 n=570n=567 Study 060 US n=459 Study 033 Latin America n=730n=124 Immuno,Safety Efficacy, Safety,Immuno Efficacy, Safety,Immuno Immuno,Safety Efficacy, Safety,Immuno Efficacy, Safety,Immuno Study 036 Europe n=2646n=1348 Study 007 Singapore n = 1158 n=653n=653 Study 048Finland n=100 n=50 Study 007 Singapore n = 1158 n=653n=653 Study 036 Europe n=2646n=1348 Study 048Finland n=100 n=50 Summary of Clinical Studies in BLA

  19. Rotarix Clinical DevelopmentPivotal & Supportive Studies • Randomized, blinded, prospective, placebo-controlled (10 of 11 studies) • Healthy infants, range 5 to 17 weeks at 1st dose (ph III 6 to 14 weeks); 2nd dose 1-2 months later • Efficacy evaluated through 2 years/RV seasons after vaccination • Safety evaluated in all studies (study 023 powered for IS assessment) • Immunogenicity typically evaluated one month after 2nd dose • Coadministration of routine infants vaccines: allowed in 9 of 11 studies

  20. Clinical Trial Data to be Presented Efficacy • Phase III Latin America • Phase III Europe Immunogenicity • Seroconversion and Vaccine Take • Coadministration with US licensed Vaccines • Fecal Antigen and Live Virus Shedding Safety • Intussusception • Integrated Summary of Safety: SAEs • Events of Clinical Interest • Integrated Summary of Safety: Reactogenicity • Reactogenicity: Europe, US & Canada

  21. Clinical Trial Data to be Presented Efficacy • Phase III Latin America • Phase III Europe Immunogenicity • Seroconversion and Vaccine Take • Coadministration with US licensed Vaccines • Fecal Antigen and Live Virus Shedding Safety • Intussusception • Integrated Summary of Safety: SAEs • Events of Clinical Interest • Integrated Summary of Safety: Reactogenicity • Reactogenicity: Europe, US & Canada

  22. Study 023: Phase III Study in Latina & Finland18 sites in 12 countries ~63,000 infants Dominican Republic 4056 (6.4%) Mexico 13245 (20.9%) Panama 4061 (6.4%) Honduras 4195 (6.6%) Venezuela 4250 (6.7%) Nicaragua 4057 (6.4%) Brazil 3218 (5.1%) Colombia 3910 (6.2%) Peru 12044 (19.0%) Argentina 4671 (7.4%) Chile 3458 (5.5%) Finland 2060 (3.3%) • LA: efficacy & safety • Finland: safety only

  23. Study 023: Phase III Safety & Efficacy Study in Latin America and Finland Rotarix N=31,673 N=63,225infants age 6-13 weeks randomized (1:1) 1st Dose 2nd Dose Placebo N=31,552 month 0 Month 1-2 Month 2-4 Safety surveillance (N=63,225) Month 9-10 1 yr Efficacy analysis (ATP N=17,867) Month 21-22 2 yr Efficacy analysis (ATP N=14,237) Routine immunizations were co-administered according to local regulations Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354:11-22

  24. Efficacy Latin America (Study 023) Primary Efficacy Objective • To determine if 2 doses of Rotarix can prevent severe RV GE caused by circulating RV strains starting from 2 weeks after dose 2 until 1 year of age Secondary Efficacy Objectives • Efficacy against G1 and non-G1 serotypes • Efficacy using Vesikari severity scale • Efficacy through 2 years of age

  25. Efficacy Latin America (Study 023) RV GE Case Definition • “Severe GE”: diarrhea (≥3 loose stools in 24 hrs) with or without vomiting that required hospitalization and/or re-hydration therapy in a medical facility [Clinical Case Definition] • RV detection by ELISA • Type determination by RT-PCR followed by reverse hybridization assay (or optional sequencing as needed) • Discrimination between G1 vaccine virus and wild-type G1 RV

  26. Efficacy Latin America (Study 023) Efficacy Endpoints • Severe RV GE during 1st year efficacy period • Clinical Case Definition • Vesikari scale: based on intensity and duration of diarrhea, vomiting, fever, dehydration and type of treatment; score ≥11 = “severe” • Efficacy against RV hospitalizations, all-cause severe GE • Type-specific efficacy • Second year efficacy

  27. Efficacy Latin America (Study 023) From 2 weeks post-dose 2 until 12 months of age (ATP cohort) 85% [71;93] 85% [72;92] 85% [70;94] 40% [28;50] 12V:77P 11V:71P 9V:59P 183V:300P randomization 1:1

  28. Efficacy Latin America (Study 023) From 2 weeks post-dose 2 until 12 months of age (ATP cohort) From 2 weeks post-dose 2 until 24 months of age (ATP cohort) 85% [72;93] 85% [70;94] 85% [72;92] 83% [73;90] 82% [73;89] 81% [71;87] 40% [28;50] 39% [30;47] 342V:551P 28V:154P 22V:127P 32V:161P randomization 1:1

  29. Type-specific Efficacy Latin America (Study 023) - severe RV GE From 2 weeks post-dose 2 until 24 months of age (ATP cohort) 87% [73;94] 82% [65;92] 79% [25;96] 62% [4;87] 39%* [-112;84] 9V:66P 10V:55P 5V:8P 3V:14P+ 7V:18P + one episode was P[6] randomization 1:1 *Not statistically significant

  30. Study 036: Phase III Study in Europe124 Sites in 6 EU Countries ~4000 Infants Finland74% Germany7% CzechRepublic7.5% France3.7% Italy0.6% Spain7.5%

  31. Study 036: Phase III Safety & Efficacy Study in Europe Rotarix N=2,646 N=3,994infants age 6-14 wks randomized (2:1) 1st dose 2nd dose Placebo N=1,348 Month 0 Months 1–2 Months 7-9 Season 1 Efficacy analysis (ATP N=3,874) Months 19-21 Season 2 Efficacy analysis (ATP N=3,848) Co-administered with DTaP-HepB-IPV/Hib (all), PCV7 (subset), MenC (subset) Vesikari T et al. Lancet 2007;370:1757-63

  32. Efficacy Europe (Study 036) Primary Efficacy Objective • To determine if 2 doses of Rotarix can prevent any RV GE caused by circulating RV strains starting from 2 weeks after dose 2 until end of the first RV season post-vaccination Secondary Efficacy Objectives • Efficacy against severe RV GE • Efficacy against G1 and non-G1 serotypes • Efficacy against RV hospitalizations • Efficacy against medically-attended RV GE • Efficacy through 2 RV seasons post-vaccination

  33. Efficacy Europe (Study 036) RV GE Case Definition • GE: diarrhea (≥3 loose stools in 24 hrs) with or without vomiting • Severity assigned using Vesikari scale; score ≥11 = “severe” • RV detection by ELISA • Type determination by RT-PCR followed by reverse hybridization assay (or optional sequencing as needed) • Discrimination between G1 vaccine virus and wild-type G1 RV

  34. Efficacy Europe (Study 036) Efficacy Endpoints • Any and Severe RV GE during 1st RV season • Efficacy against RV hospitalizations, medically-attended RV, all-cause GE hospitalizations • Type-specific efficacy • Second RV season efficacy • Efficacy from dose 1 to dose 2

  35. Efficacy Europe (Study 036) From 2 weeks post-dose 2 until end of the 1st RV season (ATP cohort) 100% [82;100] 96% [90;99] 92% [84;96] 87% [80;92] 75% [46;89] 0V:12P 10V:62P 11V:22P 5V:60P 24V:94P randomization 2:1

  36. Efficacy Europe (Study 036) 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) 100% [82;100] 96% [90;99] 96% [84;100] 92% [84;96] 90% [85;94] 87% [80;92] 84% [77;89] 79% [73;84] 75% [46;89] 72% [53;83] 85V:204P 24V:127P 2V:25P 41V:128P 27V:48P randomization 2:1

  37. Efficacy Europe (Study 036) From Dose 1 up to before Dose 2 (Total Vaccinated Cohort) 100% [-23;100] 90% [9;100] 1V:5P 0V:3P TVC = all subjects who received at least one dose regardless of protocol adherence randomization 2:1

  38. Type-specific Efficacy Europe (Study 036) - Severe RV GE From 2 weeks post-dose 2 until end of the 2nd RV season (ATP cohort) 96% [90;99] 95% [68;100] 94% [53;100] 86% [24;99] 85% [72;93] 2V:7P* 1V:8P 1V:11P 13V:44P+ 4V:57P * P genotype not typable for one episode, + P[8] genotype not detected for one episode randomization 2:1

  39. Summary of Efficacy • Rotarixprevents: • Severe RV GE disease (96% EUR; 85% LA) • Any RV GE disease (87% EUR) • RV GE hospitalizations (100% EUR: 85% LA) • Medically attended RV GE (92% EUR) • RV GE as early as dose 1 (90% EUR) • Rotarixprevents RV GE caused by G1, G2, G3, G4 and G9 strains • Rotarix efficacy persists through 2 years/seasons after vaccination

  40. Clinical Trial Data to be Presented Efficacy • Phase III Latin America • Phase III Europe Immunogenicity • Seroconversion and Vaccine Take • Coadministration with US licensed Vaccines • Fecal Antigen and Live Virus Shedding Safety • Intussusception • Integrated Summary of Safety: SAEs • Events of Clinical Interest • Integrated Summary of Safety: Reactogenicity • Reactogenicity: Europe, US & Canada

  41. Immunogenicity – Seroconversion Serum anti-Rotavirus IgA Response • Seroconversion = ≥20 U/mL in subjects RV negative prior to 1st dose • Seroconversion after dose 2 in phase III pivotal efficacy studies: • study 036 (Europe): 681/787 = 87% • study 023 (Latin America): 302/393 = 77% Efficacy against severe RV GE paralleled, but always higher compared to antibody response

  42. Immunogenicity – “Vaccine Take” • Vaccine take: Seroconversion and/or RV stool antigen detection in subjects RV negative prior to 1st dose (≥106 CCID50)

  43. Immunogenicity – Coadministered VaccinesUS Study 060 • Randomized 1:1, controlled, open label • 1º Objective: Non-inferiority immunogenicityRotarix + coads vs. coads alone • N=484 (1:1)

  44. Immunogenicity – Coadministered VaccinesUS Study 060 Pre-specified non-inferiority criteria met for all 17 coadministered antigens: • anti-PRP, anti-HBsAg, anti-poliovirus 1, 2 & 3, anti-D and anti-T: LL of 95% CI for the treatment difference in seroprotection rate  -10% • anti-PT, anti-FHA and anti-PRN: LL of 95% CI for the GMC ratios 0.67 • S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F & 23F: LL of 95% CI for the GMC ratios 0.5

  45. Viral Shedding • RV antigen excretion is a feature of natural RV infection • Following vaccination antigen excretion is expected; indication of vaccine activity • Methodology • Stool RV antigen detected by ELISA • Stool live attenuated RV detected by cell culture

  46. Fecal Antigen* Shedding Study Rota-033+Columbia, Mexico, Peru Dose 1 (n=24-26) Dose 2 (n=23-26) * ELISA positive+ Dose Conc ≥106.5 CCID50n = number of subjects with available results

  47. Live Virus Shedding in VaccineesDay 7 post-dose 1 *all ELISA positive samples with remaining stool cultured for live virus

  48. Immunogenicity Summary • Rotarix is immunogenic • Rotarix does not negatively impact the immune response to the antigens present in: • Pediarix (DTaP-HepB-IPV), Prevnar(7 valent pneumococcal) and ActHIB(PRP) • Live virus shedding: ~26% of subjects at 7 days after first dose in two clinical trials

  49. Clinical Trial Data to be Presented Efficacy • Phase III Latin America • Phase III Europe Immunogenicity • Seroconversion and Vaccine Take • Coadministration with US licensed Vaccines • Fecal Antigen and Live Virus Shedding Safety • Intussusception • Integrated Summary of Safety: SAEs • Events of Clinical Interest • Integrated Summary of Safety: Reactogenicity • Reactogenicity: Europe, US & Canada

  50. Study 023: Phase III Safety & Efficacy Study in Latin America and Finland Rotarix N=31,673 N=63,225infants age 6-13 weeks randomized (1:1) 1st Dose 2nd Dose Placebo N=31,552 month 0 Month 1-2 Month 2-4 Safety surveillance (N=63,225) Month 9-10 1 yr Efficacy analysis (ATP N=17,867) Month 21-22 2 yr Efficacy analysis (ATP N=14,237) Routine immunizations were co-administered according to local regulations Ruiz-Palacios G. et al. N. Engl. J. Med. 2006; 354:11-22

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