Novartis Vaccines - Influenza A H1N1v vaccine development Theodore F Tsai MD MPH July 23, 2009 DHHS supported influenza cell culture vaccine production facility, Holly Springs, N Carolina

2 Agenda  Novartis portfolio of influenza vaccines MF59™ oil-in-water emulsion adjuvant H5N1, MF59-adjuvanted vaccine, egg-derived (AFLUNOV ® /FOCETRIA ® ) H5N1, MF59-adjuvanted vaccine, cell culture-derived (OPTAFLU ® platform)  H1N1v vaccine clinical studies U.S.-licensed Fluvirin ® egg-based platform Europe-licensed/investigational platforms -FOCETRIA, egg-derived -Cell culture-derived  H1N1v product supply

3 Novartis seasonal and pandemic influenza vaccines VaccineLicensureFormulationIndication H5N1 subclades H1N1v Trials Unadjuvanted, trivalent inactivated vaccine, egg-derived FluvirinUSSubunit4+ years 1 (trial) 1, 2.2, 2.3 (stockpiled) +/- MF59 AgrippalEx-US/US BLASubunit6m + Adjuvanted seasonal and prepandemic/pandemic, egg-derived FLUAD ® Europe, othersSubunit65+ years AFLUNOV ® Europe, US In development Subunit 7.5 μg18+ years1, 2.2 (trials) FOCETRIA Europe Mock-up pandemic Subunit 7.5 μg18+ years (+ 6 months) +/- MF59 Cell culture-derived seasonal and pandemic OPTAFLUEurope- SeasonalSubunit18+ years2.1 (trial) Un-named H1N1v Germany CTASubunit(6+ months) +/- MF59

4 Multiple potential advantages of MF59 adjuvant in pandemic and seasonal influenza vaccines :NCT Vesikari T (submitted) 97 Toddlers 6-<36 mo (n-131) 97 Children 3-<9 y (n=91) Geometric mean ratio (D43/D1) 97 Toddlers 6-<36 mo (n=134) 97 Children 3-<9 y (n=91) 89 Adolescents 9-17 y (n=89) Adolescents 9-17 y (n=89) Toddlers 6-35 mo (n=134) 117 Children 3-8 y (n=91) 67 Adolescents 9-17 y (n=89) Seroprotection (%) Seroconversion (%) CHMP benchmarks are for adults Seroprotection rateSeroconversion rate GMTs AFLUNOV is not a licensed vaccine  A component of seasonal influenza vaccine FLUAD * for adults >65 years old, licensed since 1997 More than 45 million doses distributed Controlled clinical trial data on >33,000 subjects Ongoing FLUAD - active/placebo controlled efficacy trial in 3, month old subjects No safety signals in either the clinical trial database or in pharmacovigilance.  Adjuvanted vaccine provides higher and broader antibody responses Cross-reactive antibody responses against antigenically drifted seasonal strains Broadly cross-reactive responses against the majority of H5N1 subclades Allows for antigen sparing HI antibody response against an homologous H5N1 Vietnam strain at day 43 Vaccine contained 7.5 µg HA and full MF59 dose MF-59 oil in water emulsion adjuvant HI antibody fold-rise

5 Antigen- and MF59 dose-sparing of MDCK cell culture- derived-Indo/5/2005(H5N1) subunit vaccine Day 43 HI responses, 21 days after second dose, in healthy young adults NCT Keitel W et al (submitted) * Compared to MF59 content in EMEA- licensed MF59- adjuvanted seasonal influenza vaccine N HA antigen (µg dose) MF59*

6 MF59 Clinical Database Total number of subjects in controlled clinical studies (as of June 2009) Influenza StudiesNon-influenza Studies Combined Age Group(+)MF59(-)MF59(+)MF59(-)MF59(+)MF59(-)MF59 Children/Adolescents Adults yrs Adults ≥65 yrs Subjects with underlying medical conditions N/A Overall  No increase in risk of SAEs, new onset of chronic disease, autoimmune disorders in pooled analysis of 94 trials with 6 month follow-up - safety analysis submitted to CBER  Pediatric and H5N1 trials under oversight of Independent Data Monitoring Committees  Large scale observational study of 75,000 senior adults, Italy Novartis Data on File

7 Agenda  Novartis portfolio of influenza vaccines MF59 oil-in-water emulsion adjuvant H5N1 vaccine, MF59 adjuvanted, egg-derived (AFLUNOV/FOCETRIA) H5N1 vaccine, MF59 adjuvanted, cell culture-derived (OPTAFLU platform)  H1N1v vaccine clinical studies U.S.-licensed Fluvirin egg-based platform Europe-licensed/investigational platforms -FOCETRIA, egg-derived -Cell culture-derived  H1N1v product supply

8 Fluvirin H1N1v Vaccine Overview of clinical trials under US IND  Safety monitoring for one year Blood samples for clinical laboratory safety measurements during treatment period  Immunogenicity – HI responses Various intervals between Dose 1 and Dose 2 Weekly samples to detect early responses  Additional trials and observational studies under discussion  Pilot and pivotal studies Subject age Formulation years years>65 years Unadjuvanted Adjuvanted

9 Fluvirin H1N1v - Pilot clinical trial Trial design Vaccine Formulation Vaccination Schedule Age Group, Number of Subjects Children yrs Children yrs Adults yrs 15 µg HA unadjuvantedD1, D µg HA unadjuvantedD1 (2 doses, 1/arm) µg HA + 100% MF59D1, D µg HA + 100% MF59D1, D µg HA + 100% MF59D1 (2 doses, 1/arm)  First subject, first visit ~Aug 17  First interpretable serological result, dose 1 – mid-Sep  First interpretable serological result, dose 2 – late-Sep  Completed Clinical Study Report – mid-Nov

10 Fluvirin H1N1v – Vaccine registration studies Trial design Adult & elderly pivotal trial: N = 2,380 Pediatric trial, 3y – 9 years: N = 1,190 Antigen Dose 1, Day 1, Day 22 MF59 Dose none75% Dose 2 100% Dose yrs ≥65 yrs yrs ≥65 yrs yrs ≥65 yrs 7.5 µg HA - N µg HA - N µg HA - N170 1.Antigen doses are nominal 2.3/4 dose refers to MF59 dose including 7.31 mg squalene and full dose refers to MF59 dose including 9.75 mg squalene. “Full dose” refers to the dose contained in the licensed seasonal trivalent influenza vaccine, Fluad ® 3.75% dose refers to MF59 dose including 7.31 mg squalene and 100% dose refers to MF59 dose including 9.75 mg squalene; quantities relate to the content of MF59 in the licensed seasonal influenza vaccine, Fluad ®  First subject, first visit ~ Aug 27  First interpretable serological result, dose 1 – late-Oct/early Nov  First interpretable serological result, dose 2 – early Nov/mid Nov  Completed Clinical Study Report – mid-Dec/late-Dec

11 H1N1v vaccines in Europe Focetria and Cell derived-vaccines - Trial Overview Focetria H1N1v  Vaccine may be licensed based on manufacturing data  2 studies planned 15 µg unadjuvated vs. lower doses, adjuvanted Separate adult & pediatric studies (6m-17y & >18+y) One year booster  Sequential immunization with H1N1v before or after plain or adjuvanted seasonal TIV Cell culture- derived H1N1v  Leister University pilot trial 15 ug unadjuvanted vs lower doses, adjuvanted, various schedules First subject, first visit - July 23 Earliest result - mid-Sep  2 pivotal studies planned 15 µg unadjuvanted vs. lower doses adjuvanted Separate adult & pediatric studies (6m-17y & >18y) One year booster dose

12 Agenda  Novartis portfolio of influenza vaccines MF59 oil-in-water emulsion adjuvant H5N1 vaccine, MF59 adjuvnated, egg-derived (AFLUNOV/FOCETRIA) H5N1 vaccine, MF59 adjuvanted, cell culture-derived (OPTAFLU platform)  H1N1v vaccine clinical studies U.S.-licensed Fluvirin egg-based platform Europe-licensed/investigational platforms -FOCETRIA, egg-derived -Cell culture-derived  H1N1v product supply

13 H1N1v Vaccine Supply  Novartis has committed Liverpool site to produce US supply through end of year  Bulk production has commenced already  Goal is for 90M 15 µg bulk doses produced by Nov 30, based upon yields Fill / finish production will proceed upon U.S. Government formulation decision First doses available 4-6 weeks after fill / finish decision  Antigen production yields are below levels for seasonal strains NVD continues to optimize process Will also evaluate alternate strains / reassortants to improve yield

14 Summary  Dose ranging clinical trials of H1N1v vaccines, with/without MF59 adjuvant, produced on Egg-based Fluvirin platform – US Egg-based Focetria platform - Europe Cell-derived platform - Europe  Data from the Fluvirin-H1N1v pilot study provided on a rolling basis Preliminary serological results of dose 1, 1 week response available mid-Sep Data on all IND studies projected for mid-Nov – late-Dec  Data from first cell culture-derived vaccine pilot study projected mid-Sept