Clinical overview of GSK s AS04 adjuvanted vaccine: data up to 6.4 years

Transcription

1 Clinical overview of GSK s AS04 adjuvanted vaccine: data up to 6.4 years Gudrun Maechler Director, Clinical & Medical Affairs Europe & Cervarix GSK Biologicals

2 Presentation Outline HPV immunology Immunogenicity Efficacy Safety Conclusions

3 HPV lifecycle in the cervical epithelium Cervical canal Cervical epithelium Virus particles are assembled and virus released Virus uses host cell machinery to replicate viral DNA and express virally encoded proteins HPV infects basal layer of the cervical epithelium Frazer IH et al. Pediatr Infect Dis J 2006;25:S65 S81.

4 HPV lifecycle and immune evasion HPV has many immune evasion mechanisms 1 : Cervical canal Cervical epithelium Viral lifecycle occurs within epithelium No viraemia No cell death No inflammation Local immunosuppression caused by viral proteins 1. Stanley M et al. Vaccine 2006;24S1:S1/16 S1/22;

5 HPV vaccines prevent infection via neutralising antibodies HPV vaccination focuses on preventing HPV infection through generation of neutralising antibodies Neutralising antibodies bind to sites on the viral capsid and prevent infection of host cells 1 HPV infects target cell in basal layer of the cervical epithelium Basal cell layer of cervical epithelium Infection The major basis of protection against infection [following vaccination] is neutralising antibody WHO Neutralising antibodies prevent HPV from infecting basal epithelial cells X No infection 1. Stanley M et al. Vaccine 2006;24 Suppl 3:S106 S113; 2. WHO Department of Immunization, Vaccines and Biologicals 2007.

6 High neutralising antibody levels in the cervix are thought to mediate protection from HPV infection Cervical canal Cervical epithelium Blood vessel Low antibody levels following natural infection Key requirement of vaccine: high serum antibody levels that travel to site of infection Higher serum antibody titers lead to higher antibody levels in the cervico-vaginal secretions (CVS) at the site of infection 1,2 1. Stanley M et al. Vaccine 2006;24 Suppl 3:S106 S113; 2. Poncelet S et al. 24th International Papillomavirus Conference 2007;Abstract PS19-25.

7 Cervarix Development Strategy No compromise on Cervical Cancer protection Inclusion of oncogenic HPV types only- avoid risk of interference by addition of other types Highly purified antigens assembled in VLPs Adjuvant enhances immune responses AS04 = MPL + Al(OH) 3

8 AS04 enhances the immune response AS04 provides neutralising antibody levels to both HPV 16 and 18 which are sustained at higher levels than the same vaccine adjuvanted with Al(OH) 3 GMT antibody titres (EU/ml) HPV 16 neutralising antibodies 0 * * * m Vaccination * = AS04 = Al(OH) 3 * * HPV 18 neutralising antibodies 1000 * * * m Vaccination * = AS04 = Al(OH) 3 * * Giannini SL et al. Vaccine 2006;24:

9 At least 6.4 Years high & sustained immune response for both HPV-16 & ,000 10,000 Anti-HPV HPV-16 IgG Neutralizing Antibody Responses ED 50 1, Natural infection ED ,000 10,000 1, Months Anti-HPV HPV IgG 98% of women remain seropositive for both HPV-16 & -18 up to 6.4 years Natural infection Months Titres determined on HPV-16/18 ELISA positive/dna negative subjects Harper DM. ESPID presentation 2008.

10 High antibody levels at 7 months are predicted to lead to sustained high levels over the long term The long-term persistence of HPV 18 antibodies has been predicted by mathematical modelling based on actual antibody levels up to 5.5 years following Cervarix vaccination 1 Long-term antibody levels predicted by two different models are shown Anti-HPV 18 antibody titre (EU/ml) 100,000 10,000 1, Data from individual subjects Anti-HPV 18 Natural Infection: 22.7 EU/ml Months since first dose Predicted antibody titers Fraser model Piecewise model David MB et al. Poster presented at ESPID, 2008

11 Cervarix has shown 100% efficacy against HPVrelated CIN2+ for 6.4 years HPV 16/18 related Cervarix Control Vaccine Efficacy CIN2+ n n % 95% CI Initial efficacy study 27 months NA Combined analysis initial efficacy study and extended followup 4.5 yrs yrs yrs ITT analysis n = number of subjects reporting at least one event in each group 1. Harper DM et al. Lancet. 2004; 364: Harper DM et al. Lancet 2006; 367: Presentation Gall S, AACR, Los Angeles, April 14-18, 2007, abstract Harper DM, Presented at SGO, Tampa, Florida, March 9-12, 2008.

12 Cervarix demonstrates cross-protective efficacy against HPV types 45 and 31 at 6.4 years Combined analysis initial efficacy study and extended follow-up HPV type Cervarix Control Vaccine Efficacy n n % 95 % CI HPV HPV ATP analysis n = number of subjects reporting at least one event in each group Harper DM, Presented at SGO, Tampa, Florida, March 9-12, 2008

13 HPV16/18/45 account for 90% of adenocarcinoma

14 Cervarix safety profile Data are available from a large safety database (>32,000 subjects) in a broad age range Cervarix is well tolerated with a favourable safety profile: Cervarix is generally well tolerated across all age groups rates of unsolicited adverse events, serious adverse events and autoimmune diseases are comparable in vaccine and control groups safety profile is comparable in women with and without HPV exposure prior to vaccination similar overall rates of pregnancy outcomes are seen in vaccine and control groups overall very good compliance rates are seen across all studies (>90%) GSK. Data on file 2008.

15 Summary I HPV can evade detection by the immune system natural response to HPV infection may be insufficient to fully protect women from future infection and development of cervical cancer Cervarix induces antibodies that provide sustained protection from HPV over the long term high and sustained neutralising antibodies are thought to be the best surrogate markers of a high quality immune response and long-term protection

16 Summary II Evidence on long-term efficacy of Cervarix extends to 6.4 years, the longest HPV vaccine efficacy study to date sustained high levels of neutralising antibodies are associated with 100% efficacy in preventing HPV 16- and 18-associated CIN2+ A comparative study directly comparing the immune response to Cervarix and Gardasil is underway