Licensing Pandemic Vaccines Novartis Vaccines

1. Licensing Pandemic VaccinesNovartis Vaccines Penny Heaton, MD, Global head clinical development clusters VRBPAC Washington DC, February 2012

2. Novartis Vaccines 2009 Pandemic Response Flu Cell Culture Site Ribbon Cutting Fall 2009 • July of 2009 reported successful manufacturing of A(H1N1) antigen (using wild-type strain and Cell Culture) • September of 2009 published results from A(H1N1) clinical trial • Over 15,000 subjects enrolled in controlled clinical studies • Three vaccines approved globally: • Fluvirin ® (egg,15µg, unadjuvanted) • Focetria ® (egg, 7.5µg, adjuvanted) • Celtura®(cell culture, 3.75µg, adjuvanted) • 150 million doses delivered globally • 4 production sites utilized • Liverpool site capacity dedicated to US supply | VRBPAC | Penny Heaton | Feb 2012 | Licensing Pandemic Vaccines

3. Pathways needed for licensure for Novartis Portfolio ü | Pandemic licensure pathways | February 2012 | Confidential For discussion today

4. Novartis Influenza Vaccine Products Cell Culture, Adjuvanted, Quadrivalent Vaccines in Development Fluvirin® Egg Agriflu® Seasonal Fluad® (Adjuvanted) Quadrivalent (AABB) Optaflu® Cell Culture 2009 A(H1N1) Egg 2009 A(H1N1) (Adjuv.) Aflunov® (Adjuvanted) (Pre)-Pandemic Celtura® (Adjuvanted) Cell Culture US Approved FCC A(H5N1) (Adjuv.) Not US Approved | VRBPAC | Penny Heaton | Feb 2012 | Licensing Pandemic Vaccines

5. Novartis examples of pandemic licensure pathways | VRBPAC | Penny Heaton | Feb 2012 | Licensing Pandemic Vaccines

6. 1. Fluvirin A(H1N1) +/- Adjuvant (1/2)Pandemic vaccine with virus subtype included in licensed seasonal influenza vaccine • Background • Fluvirin seasonal vaccine licensed 1988 • 2009 A(H1N1) studies (with and without MF59 ® adjuvant) based on CBER discussions for pandemic licensure (5,500 subject database under IND from 6 months to 65+ years) • Safety data available from MF59 database of >37,000 controlled subjects • Unadjuvanted H1N1 pandemic vaccine approved as an annual strain change | VRBPAC | Penny Heaton | Feb 2012 | Licensing Pandemic Vaccines

7. 1. Fluvirin A(H1N1) +/- Adjuvant (2/2)Pandemic vaccine with virus subtype included in licensed seasonal influenza vaccine • FDA Input • Type C meeting to discuss licensure of adjuvanted pandemic vaccine for individuals aged 6 months and older based on A(H1N1) vaccine clinical trial data • As the influenza virus type/subtype responsible for next pandemic unknown, could not provide assurance that strain change mechanism of approval will be appropriate for next pandemic, or that additional studies would not be needed. • Pathway going Forward • Novartis did not pursue indication for adjuvanted pandemic vaccine | VRBPAC | Penny Heaton | Feb 2012 | Licensing Pandemic Vaccines

8. 2. Aflunov – Adjuvanted Egg Based A(H5N1) (1/2)Pandemic vaccine against subtypes of pandemic potential manufactured by a licensed process • Background • European Commission approved in Nov 2010 • US seasonal platform (Agriflu) licensed in 2009 • Completed and ongoing trials of >9,600 subjects across all age ranges 6 months and older • Highly immunogenic at low doses with acceptablesafety and tolerability profile • Cross-reactivity against other H5 clades; immunologic memory observed with boosting several years after priming | VRBPAC | Penny Heaton | Feb 2012 | Licensing Pandemic Vaccines

9. 2. Aflunov – Adjuvanted Egg Based A(H5N1) (2/2) Pandemic vaccine against subtypes of pandemic potential manufactured by a licensed process • FDA Input • During Pre-IND discussions Novartis urged to continue development, and that a “small clinical study would be required” • IND submitted; CBER did not accept proposed clinical study. • Revised CBER guidance: a clinical endpoint efficacy study using an adjuvanted seasonal vaccine could support traditional approval of adjuvantedmonovalent pandemic subtype vaccines • Pathway going Forward • Novartis elected to defer follow-up discussions to focus on A(H1N1) vaccine | VRBPAC | Penny Heaton | Feb 2012 | Licensing Pandemic Vaccines

10. 3. Flu Cell Culture H5N1 (1/2)Pandemic vaccine with subtypes of pandemic potential manufactured by un-licensed process • Background • Cell culture projects supported by BARDA (Contract Nos. HHS100200600012C and HHS100200700030C) • Global A(H1N1) Experience • Celtura (FCC A(H1N1) + Adjuvant) licensed for individuals 6 months of age and older • WHO pre-qualified over 25 million doses distributed in 10 countries • Substantial dose-sparing: 3.75 μg per 0.25 ml dose with A(H1N1) plus MF59 adjuvant • US A(H5N1) Program: Completed dose ranging study of A/Indonesia/5/2005 clade 2.1 antigen and MF59 in 720 subjects 18-40 years, Phase II study ongoing | VRBPAC | Penny Heaton | Feb 2012 | Licensing Pandemic Vaccines

11. 3. Flu Cell Culture A(H5N1) (2/2)Pandemic vaccine with subtypes of pandemic potential manufactured by un-licensed process • FDA input • FDA recommended seasonal trivalent cell culture vaccine should be licensed before an A(H5N1) vaccine • Comparability study between Ph I material (Indonesia strain) and Ph III material (Turkey or Egypt strains) required • Recommended 12-month follow-up and an assessment of a booster dose • Pathway going forward • Novartis to begin multiple studies to expand age indication to 6 months and older in 2012 | VRBPAC | Penny Heaton | Feb 2012 | Licensing Pandemic Vaccines

12. Open Questions • Under what conditions would a strain change mechanism of approval be appropriate for a next pandemic? • What types of clinical studies, in what age ranges, are required for licensure in a pandemic or prepandemic setting? • By definition, it is not possible to demonstrate effectiveness prior to pandemic • Also difficult to demonstrate effectiveness during pandemic • HI antibody response is an accepted surrogate marker of immunity and is reasonably likely to predict clinical benefit • What post-licensure studies would be required? | VRBPAC | Penny Heaton | Feb 2012 | Licensing Pandemic Vaccines