Toelichting Sanofi Pasteur MSD GARDASIL VVOG – Lentevergadering Gent, 03-03-2007 Toelichting Sanofi Pasteur MSD GARDASIL Patrick Dhont Medical Affairs Manager

Wat nieuws te melden over Gardasil®? Samenstelling Gardasil® Nieuwe werkzaamheidsgegevens Samenvatting registratie Gardasil® in EU – update veiligheid USA Impact van vaccinatie met Gardasil®

Proprietary Amorphous Aluminium Hydroxyphosphate Sulphate adjuvant for optimal fit with VLPs AAHS adjuvant further focuses the immune response & directs it to produce specific antibodies + Amorphous Aluminium Hydroxyphosphate Sulphate* + Aluminium Hydroxide *Amorphous Aluminium Hydroxyphosphate Sulphate - AAHS 225 μg of Aluminium [1] Sanofi Pasteur MSD, data on file [2] Shank-Retzlaff M et al. Human Vaccines 2006; 2(4):147-154

Selection of AAHS* Over Aluminum Hydroxide as Adjuvant for Gardasil® AAHS stabilises VLPs and binds more VLPs than other aluminium adjuvants1,2 AAHS maximises immuno- genicity of VLPs1 100 107 95 90 % of [HPV16 VLPs bound to Al] out of [Total HPV16 VLPs] ELISA IgG anti-HPV16 L1 (GMT) 3 weeks post dose 2 85 AAHS 80 Aluminium Phosphate Aluminium Hydroxide 75 106 70 1 10 Aluminium Hydroxide Aluminium Phosphate AAHS [Total HPV16 VLPs]/[Total Aluminum] (w/w) Binding capacity of different aluminium adjuvants to HPV 16 VLP Antibody response to HPV 16 VLP formulations with different Aluminium adjuvants measured in vivo in Balb c mice * Amorphous Aluminium Hydroxyphosphate Sulfate, 225 μg of Aluminium [1] Sanofi Pasteur MSD, data on file [2] Shank-Retzlaff M et al. Human Vaccines 2006; 2(4):147-154

Wat nieuws te melden over Gardasil®? Samenstelling Gardasil® Nieuwe werkzaamheidsgegevens Samenvatting registratie Gardasil® in EU – update veiligheid USA Impact van vaccinatie met Gardasil®

Disease related to types 6,11,16,18 High efficacy against Cervical Cancer and other HPV diseases before Cervical Cancer & beyond the Cervix in large clinical studies Disease related to types 6,11,16,18 Gardasil® per protocol efficacy analysis Cervical Cancer (CIN*2/3 and AIS**, primary endpoint) 100% 95% CI [81,100]1 Pre-cancerous (CIN*2/3, primary endpoint) & Potentially pre-cancerous cervical lesions (CIN*1) 100% 97.5% CI [87,100]2,† Pre-cancerous vulvar lesions (combined analysis) ------------------------------------------------------------------------------------------------------------------- Pre-cancerous vaginal lesions (combined analysis) 100% 95% CI [42,100]2 ------------------------------------------------------------ 100% 95% CI [31,100]2 Genital warts (primary endpoint) 100% 95% CI [78.5,100]2‡ In women exposed to one or more vaccine virus types, Gardasil® was still up to 100% efficacious (95% CI [55,100]) against disease caused by the remaining vaccine types to which the women had not been exposed3 [1] Ault K, Abstract, European Cancer Conference (ECCO) November 2nd, 2005, Paris France [2] Joura EA et al. Oral presentation and abstract, 18th International Congress on Anti Cancer Treatment, Paris, France, 7th February 2007 [3] Ferris, D. Abstract, EUROGIN meeting, Paris, France, 26 April 2006 (3 injections of the vaccine at day 1, month 2 and month 6 of the study with a median duration of follow-up between 2 and 4 years) * Cervical Intraepithelial Neoplasia ** Adenoma Carcinoma in Situ † 95,2% (95% CI [87.2,98.7]) in the combined analysis of several clinical studies ‡ 98.9%(95% CI [93.7,100]) in the combined analysis of several clinical studies

Gardasil® Yields Higher Neutralizing Anti-HPV Antibodies in Baseline Seropositive Subjects Vaccine (PCR–, Sero+) Placebo (Per Protocol) Vaccine (Per Protocol; PCR–, Sero–) GMT (nMU/mL) 3 7 12 18 24 30 36 1 10 100 1,000 10,000 Month (n=13) (n=184) (n=14) (n=177) (n=170) (n=6) HPV 6 HPV 11 HPV 16 HPV 18 (n=9) (n=196) (n=193) 1/Villa/p. 5578/Figure 3 These results suggest that women who were baseline anti-HPV positive developed a booster response to vaccination 1/Villa/p. 5578/col 1/¶2,3. Adapted from Villa L., Ault K., Giuliano A. et al, Vaccine 2006; 24:5571–5583 1/Villa/p. 5578/col 2//¶1,2.

Placebo groep Future I en II studies wordt gevaccineerd met Gardasil® Aankondiging op 27-02-2007 In het kader van de hoge werkzaamheid van Gardasil® waargenomen in de grote klinische studies FUTURE I en II, gaf de onafhankelijke Data and Safety Monitoring Board (DSMB) de aanbeveling om vrouwen in de placebogroep te vaccineren met Gardasil® De DSMB adviseerde om de studies zo snel mogelijk te beëindigen om deze vrouwen snel te laten genieten van de voordelen van de vaccinatie met Gardasil® In totaal verwacht men dat er ongeveer 4.300 vrouwen zullen gevaccineerd worden in Europese studiecentra en de doelstelling is om de vaccinatie te voltooien tegen eind 2007 Media Reports 22 & 23-02-2007

Gegevens van Gardasil® op komst Nieuwe follow-up data fase III studies met Gardasil® Publicatie fase III studies Klinische data cross-protection met Gardasil ® (fase III data set) Eerste klinische data van de ‘mid-adult women’ fase III studie (24-45 jaar)

Wat nieuws te melden over Gardasil®? Samenstelling Gardasil® Nieuwe werkzaamheidsgegevens Samenvatting registratie Gardasil® in EU – update veiligheid USA Impact van vaccinatie met Gardasil®

Indications of Gardasil® 1 Breakthrough in the prevention of Cervical Cancer & other HPV diseases before Cervical Cancer and beyond the Cervix endorsed by EMEA Indications of Gardasil® 1 Prevention of Cervical Cancer Prevention of Pre-cancerous Cervical Lesions (CIN*2/3) Prevention of Pre-cancerous Vulvar Lesions (VIN**2/3) Prevention of Genital Warts -------------------------------------------------------------------------------------- Additional properties2 Efficacious against Potentially Pre-canc. Cerv. Lesions (CIN*1) Reduction of Pre-cancerous Vaginal Lesions (VaIN***2/3) seen in clinical studies caused by HPV types 6,11,16,18 2005 2006 2007 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Goedkeuring op 9 maanden i.p.v. gebruikelijke 13-15 maanden Standard plan Achieved [1] Indication of Gardasil in the European Union: Prevention of high-grade cervical dysplasia (CIN 2/3), cervical carcinoma, high-grade vulvar dysplastic lesions (VIN 2/3), and external genital warts (condyloma acuminata) causally related to Human Papillomavirus (HPV) types 6, 11, 16 and 18. Section 4.1 (Therapeutic Indications) of Summary of Product Characteristics, SPC [2] Section 5.1 (Pharmacodynamic properties) of Summary of Product Characteristics, SPC * Cervical intraepithelial neoplasia ** Vulvar intraepithelial neoplasia *** Vaginal intraepithelial neoplasia

ACIP meeting 22-02-2007 CDC* heeft ACIP** een update van de bijwerkingen gegeven zoals opgetekend in een federaal meldingssysteem voor bijwerkingen van vaccins (VAERS)*** tussen juni 2006 en januari 2007 in de USA 2.1 miljoen dosissen Gardasil® gedistribueerd in USA Gerapporteerde bijwerkingen Gardasil® gelijk aan andere vaccins Gerapporteerde bijwerkingen zoals beschreven in studies met Gardasil® Voor CDC geen nood aan bijkomende waarschuwingen voor Gardasil® * Centres fo Disease Control and Prevention ** Advisory Committee on Immunization Practices *** Vaccine Adverse Event Reporting System

Wat nieuws te melden over Gardasil®? Samenstelling Gardasil® Nieuwe werkzaamheidsgegevens Samenvatting registratie Gardasil® in EU – update veiligheid USA Impact van vaccinatie met Gardasil®

Dynamic transmission model (US) to estimate the impact of Gardasil® Shows year by year the impact of Gardasil® on vaccinated individuals and their sexual contacts Takes into account Herd immunity The model estimates the vaccine’s impact on the vaccinated population and its sexual contacts The model compares costs and health outcomes benefits of several strategies: Current cervical cancer screening program Gardasil® + screening: 12 year-old cohort Gardasil® + screening: 12 year-old cohort + catch up (12-24 year) Elbasha EH – Emerging Inf Dis – CDC - 2007

Assumptions Vaccination Penetration Rates Routine 12-year olds Vaccine penetration increases linearly from 0% to 70% in year 5 and beyond 12-24 year-old catch-up All cohorts (12-24): vaccine penetration increases linearly from 0% to 50% in year 5 and beyond Program stops after 5 years Elbasha EH – Emerging Inf Dis – CDC - 2007

Vaccination impact on HPV 16/18 related CIN 2/3 & cervical cancer incidence Invasive cervical cancer CIN 2/3 Temporary catch-up strategy (12-24 year) can reduce the incidence of CIN 2/3 & cervical cancer earlier Elbasha EH – Emerging Inf Dis – CDC - 2007 Assuming : lifelong protection

Vaccination impact on HPV 6/11 related genital warts (♀) incidence Temporary catch-up strategy (12-24 year) can reduce the incidence of gential warts earlier Elbasha EH – Emerging Inf Dis – CDC - 2007 Assuming : lifelong protection

Dynamic transmission model (US) Cost-effectiveness ratio HPV 6/11/16/18 vaccine + screening Incremental cost by Quality Adjusted Life Year gained (QALYs) 12-year-old females $2,964* 12-year-old females + 12-24-year-old females catch-up $4,666** Temporary catch-up strategy (12-24 year) is a very cost-effective strategy * 12 year-old females: “vaccination & screening” compared to “screening only” ** “12 yo fem. vaccination & screening + 12-24 yo catch-up” compared to “12 yo fem. vaccination & screening” Assuming lifelong protection These results do not take into account other HPV related diseases such as lesions, vaginal and vulvar cancers, nor potential cross-protection against other HPV types Elbasha EH – Emerging Inf Dis – CDC - 2007

Wat nieuws te melden over Gardasil®? Samenstelling Gardasil® Nieuwe werkzaamheidsgegevens Samenvatting registratie Gardasil® in EU – update veiligheid USA Impact van vaccinatie met Gardasil® bij de globale bevolking

Impact vaccinatie in algemene populatie (onafhankelijk van HPV status) CIN 2/3 in subjects presumably HPV infected at Day 1 CIN 2/3 in subjects presumably HPV naïve at Day 1 Barr E. – ACIP meeting June 2006

Impact vaccinatie in algemene populatie (onafhankelijk van HPV status) Barr E. – ACIP meeting June 2006

Impact vaccinatie in algemene populatie - projectie MITT 3 population – Expected time to Clinical Disease diagnoses We would expect most cases in this time frame to be women with previous infection and those who were naïve at baseline Proportion of subjects with Clinical Disease Placebo group We would expect most cases in this time frame to be women with previous clinical disease and previous infection The vaccine efficacy is illustrated by the difference between the two curves. It is different at different time points Vaccine Efficacy We would expect most cases in this time frame to be women with previous clinical disease Vaccine Efficacy GARDASIL group Length of follow up Medium term Longer term Early

Toelichting Sanofi Pasteur MSD GARDASIL VVOG – Lentevergadering Gent, 03-03-2007 Toelichting Sanofi Pasteur MSD GARDASIL Patrick Dhont Medical Affairs Manager