GSK s Candidate Influenza A (H5N1) Virus Monovalent Vaccine

Transcription

1 GSK s Candidate Influenza A (H5N1) Virus Monovalent Vaccine Regulatory Pathway for Licensure VRBPAC, February 29, 2012 Katalin Abraham, Director, US Regulatory Affairs GSK Biologicals

2 GSK s Influenza Vaccines in US Québec Process In Vaccine Development Submitted Approved Dresden Process In Vaccine Development Submitted Approved Trivalent (seasonal) FluLaval * Quadrivalent (seasonal) Accelerated e Trivalent (seasonal) Fluarix * Quadrivalent (seasonal) H1N1 unadjuvanted H1N1 H5N1 Strain change H1N1 H5N1 *approved outside of US 2

3 GSK s Adjuvanted Pandemic Influenza Vaccines (not licensed in US) Monovalent, vaccine strains recommended by the WHO Standard adult dose is 3.75 µg HA + AS03 A 10-dose Antigen vial 10-dose AS03 adjuvant system vial AS03 is an oil-in-water emulsion containing DL-αtocopherol (vitamin E), Squalene and Polysorbate 80 Mixed prior to injection Ferret H5N1 Challenge Results Protection from homologous challenge (Baras et al., Vaccine 2011) Protection from cross-clade challenge (Baras et al., PLoS one 2008) Experience with adjuvanted vaccine H5N1 >12,000 subjects H1N1 >10,000 subjects H1N1 >90 million people (post-marketing) 3

4 GSK s Influenza Vaccines in US Vaccine Québec Process In Development Submitted Approved Vaccine Dresden Process In Development Submitted Approved Trivalent (seasonal) FluLaval * Quadrivalent (seasonal) H1N1 un H1N1 H5N1 Accelerated Strain change Trivalent (seasonal) Fluarix * Quadrivalent (seasonal) H1N1 d* H5N1 Feb 2012 *approved outside of US 4

5 Q-Pan H5N1 Vaccine Composition Antigen: A/Indonesia/05/2005/PR8-IBCDC-RG2 (H5N1) Bulk manufacture follows that for seasonal FluLaval vaccine AS03 Adjuvant System Oil-in-water emulsion containing DL-α-tocopherol (vitamin E), Squalene and Polysorbate 80 Proposed indication: for active immunization for the prevention of disease in persons 18 years of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine 6

6 GSK Contracts with BARDA Development p contracts Antigen sparing contract, HHSO C Includes H5N1 and other subtypes of pandemic potential Cell culture contract, HHSO C EB66 cell substrate Stockpiling contract, HHSO I Antigens Adjuvant 22 component vaccine approach also supports NIH/BARDA evaluation of GSK s AS03 adjuvant system with another manufacturer s antigens 5

7 Q-Pan H5N1 Vaccine Development Milestones Date Milestone Jan 2007 Pre-IND Meeting Jun 2007 Initial IND Application Jul 2007 IND Active Sep 2008 Pre-BLA Meeting (Jun 2009 Submission) Apr 2009 WHO declares Phase 4 Jun 2009 WHO declares Phase 6 Jul 2010 Type C Meeting Aug 2010 WHO declares pandemic over Feb 2011 Type A Meeting Oct 2011 Type C Meeting Feb 2012 BLA submitted 7

8 Evolution of Approach for Demonstration of Clinical Benefit Observational cohort study, in response to a 2008 pandemic, using proportional hazard model to assess risk over time as cohort is vaccinated 2010 Randomized clinical trial using surrogate, i.e., adjuvanted monovalent or trivalent vaccine 2011 CBER and GSK agreement: H5N1 pandemic vaccine effectiveness can be inferred from vaccine effectiveness of adjuvanted H1N1 pandemic vaccine 8

9 Immunogenicity Bridges H1N1 Vaccine Effectiveness to H5N1 Clinical Benefit Different dosing regimens Q-PanQ H1N1: single dose Q-Pan H5N1: 2 doses, given 21 days apart Similar HI antibody responses are observed in adults (pediatric H5N1 data are pending) Seroconversion Rate w/ 95% CI 100.0% 90.1% 90.8% 80.0% 78.2% 74.0% 60.0% H1N % H1N1 64+ H5N % H5N % H1N1H1N1H5N1H5N1 Post-Vaccination Log 10 GMT w/ 95% CI H1N H1N H5N H5N H1N1 H1N1 H5N1 H5N1 9

10 Québec Process Influenza Vaccines Approved in Approved in Vaccine the US Canada Trivalent seasonal H1N1 unadjuvanted H1N1 *In Canada, 95% of the vaccine distributed was adjuvanted H1N1 10

11 Vaccine Effectiveness Studies Conducted with Arepanrix H1N1 Publication Location, Design Population Observed Effectiveness (95% CI) Van Buynder et al., New Brunswick; Community-based, 100% (80-100%) Influenza and Other Respiratory Viruses mos to <10 yrs case-control test negative study Mahmud et al., Manitoba; Population-based, 86% (75-93%) Vaccine mos case-control test negative study Skowronski et al., BMJ 2011 BC, AB, QC, ON; 6 mos Sentinel sites, case-control test negative study 93% (69-98%) 11

12 Required Regulatory Documentation for Effectiveness Studies Protocol Full clinical study report Appropriate datasets for analysis Description of the statistical methods Sample forms Information on the assays 12

13 Pandemic Vaccine Approval Pathways (from FDA Briefing Document for Feb 29, 2012 VRBPAC) Pathway for pandemic vaccine: When seasonal vaccine has accelerated approval Where subtype is not included in seasonal vaccine That contains adjuvant The clinical package for licensure application: Effectiveness data from adjuvanted pandemic influenza A/H1N1 In addition to immunogenicity and safety data for the pandemic vaccine In the population To define dose, adjuvant content, dosing regimen 13

14 Clinical Data Package for Q-Pan H5N1 BLA Pivotal studies Immunogenicity, reactogenicity and safety data (including lot consistency) 5,241 subjects, two Q-Pan H5N1 studies 3,574 subjects (licensure formulation) Vaccine effectiveness, one Q-Pan H1N1 study Supportive studies 3 Q-Pan H5N1 studies (other than proposed indication) 2 Q-Pan H1N1 studies (publications) 14

15 Two Integrated Summaries of Safety (ISS) 2009 ISS H5N1, Q-Pan and D-Pan 8 studies, 12,281 subjects 9,873 subjects: H5N1 antigen with AS03 3,574 subjects: Q-Pan H5N1 (licensure formulation) 2011 ISS H5N1 and H1N1, Q-Pan and D-Pan 28 studies, 22,521 subjects 8,0588 subjects: Quebec process antigen 4,105 subjects: Q-Pan H5N1 (licensure formulation) 15

16 Further Regulatory Guidance Would Be Beneficial i Additional pathways a Correlate of protection Use of imperfectly matched seeds Release methods 16

17 Summary GSK s portfolio of influenza vaccines includes adjuvanted pandemic subtype vaccines HI data indicate similar antibody responses to Q-Pan H5N1 and Q-Pan H1N1 vaccines Studies of vaccine effectiveness during H1N1 pandemic offer meaningful data Q-Pan H5N1 BLA has been submitted for review, including a complete clinical data package: Immunogenicity g y and safety data for Q-Pan H5N1 vaccine Effectiveness inferred from Q-Pan H1N1 Additional safety data supporting adjuvanted approach (H1N1 and H5N1) 17