Novartis Vaccines - Influenza A H1N1v vaccine development

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Novartis Vaccines - Influenza A H1N1v vaccine
development
DHHS supported influenza cell culture vaccine
production facility, Holly Springs, N Carolina

• Theodore F Tsai MD MPH
• July 23, 2009

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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

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Novartis seasonal and pandemic influenza vaccines
Vaccine Vaccine Licensure Formulation Indication H5N1 subclades H5N1 subclades H1N1v Trials H1N1v Trials
Unadjuvanted, trivalent inactivated vaccine, egg-derived Unadjuvanted, trivalent inactivated vaccine, egg-derived Unadjuvanted, trivalent inactivated vaccine, egg-derived Unadjuvanted, trivalent inactivated vaccine, egg-derived Unadjuvanted, trivalent inactivated vaccine, egg-derived Unadjuvanted, trivalent inactivated vaccine, egg-derived Unadjuvanted, trivalent inactivated vaccine, egg-derived Unadjuvanted, trivalent inactivated vaccine, egg-derived Unadjuvanted, trivalent inactivated vaccine, egg-derived
Fluvirin US US Subunit 4 years 4 years 1 (trial) 1, 2.2, 2.3 (stockpiled) 1 (trial) 1, 2.2, 2.3 (stockpiled) /- MF59
Agrippal Ex-US/US BLA Ex-US/US BLA Subunit 6m 6m
Adjuvanted seasonal and prepandemic/pandemic, egg-derived Adjuvanted seasonal and prepandemic/pandemic, egg-derived Adjuvanted seasonal and prepandemic/pandemic, egg-derived Adjuvanted seasonal and prepandemic/pandemic, egg-derived Adjuvanted seasonal and prepandemic/pandemic, egg-derived Adjuvanted seasonal and prepandemic/pandemic, egg-derived Adjuvanted seasonal and prepandemic/pandemic, egg-derived Adjuvanted seasonal and prepandemic/pandemic, egg-derived
FLUAD Europe, others Europe, others Subunit 65 years 65 years
AFLUNOV Europe, US In development Europe, US In development Subunit 7.5 µg 18 years 18 years 1, 2.2 (trials) 1, 2.2 (trials)
FOCETRIA Europe Mock-up pandemic Europe Mock-up pandemic Subunit 7.5 µg 18 years ( 6 months) 18 years ( 6 months) /- MF59
Cell culture-derived seasonal and pandemic Cell culture-derived seasonal and pandemic Cell culture-derived seasonal and pandemic Cell culture-derived seasonal and pandemic Cell culture-derived seasonal and pandemic Cell culture-derived seasonal and pandemic Cell culture-derived seasonal and pandemic Cell culture-derived seasonal and pandemic Cell culture-derived seasonal and pandemic
OPTAFLU Europe- Seasonal Europe- Seasonal Subunit 18 years 18 years 2.1 (trial) 2.1 (trial)
Un-named H1N1v Germany CTA Germany CTA Subunit (6 months) (6 months) /- MF59
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Multiple potential advantages of MF59 adjuvant in
pandemic and seasonal influenza vaccines
GMTs 688 585 344
MF-59 oil in water emulsion adjuvant

• A component of seasonal influenza vaccine FLUAD
  for adults gt65 years old, licensed since 1997
• More than 45 million doses distributed
• Controlled clinical trial data on gt33,000
  subjects
• Ongoing FLUAD - active/placebo controlled
  efficacy trial in 3,000 6-36 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

Seroprotection rate
Seroconversion rate
HI antibody fold-rise

• HI antibody response against an homologous H5N1
  Vietnam strain at day 43
• Vaccine contained 7.5 µg HA and full MF59 dose

AFLUNOV is not a licensed vaccine
NCT00537524 Vesikari T (submitted)
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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

MF59
Compared to MF59 content in EMEA- licensed
MF59-adjuvanted seasonal influenza vaccine
HA antigen (µg dose)
N 55 55 53 52 51 51
53 52 58 50 59 47
NCT00812019 Keitel W et al (submitted)
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MF59 Clinical DatabaseTotal number of subjects
in controlled clinical studies (as of June 2009)
Influenza Studies Influenza Studies Non-influenza Studies Non-influenza Studies Combined Combined
Age Group ()MF59 (-)MF59 ()MF59 (-)MF59 ()MF59 (-)MF59
Children/Adolescents 3141 3306 19 4 3160 3310
Adults 18-64 yrs 10645 937 5442 268 16087 1205
Adults 65 yrs 13577 6483 18 0 13595 6483
Subjects with underlying medical conditions 291 235 N/A N/A 291 235
Overall 27654 10961 5479 272 33136 11233

• 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
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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

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Fluvirin H1N1v Vaccine Overview of clinical
trials under US IND
Subject age Subject age Subject age
Formulation 3 - 17 years 18 - 64 years gt65 years
Unadjuvanted ? ? ?
Adjuvanted ? ? ?

• 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

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Fluvirin H1N1v - Pilot clinical trialTrial design
Vaccine Formulation Vaccination Schedule Age Group, Number of Subjects Age Group, Number of Subjects Age Group, Number of Subjects
Vaccine Formulation Vaccination Schedule Children 3 - 8 yrs Children 9 - 17 yrs Adults 18 - 64 yrs
15 µg HA unadjuvanted D1, D22 84 84 168
15 µg HA unadjuvanted D1 (2 doses, 1/arm) 56 56 56
7.5 µg HA 100 MF59 D1, D8 -- -- 56
7.5 µg HA 100 MF59 D1, D22 56 56 56
7.5 µg HA 100 MF59 D1 (2 doses, 1/arm) -- -- 56

• 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

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Fluvirin H1N1v Vaccine registration
studiesTrial design

• Adult elderly pivotal trial N 2,380
• Pediatric trial, 3y 9 years N 1,190

Antigen Dose1, Day 1, Day 22 MF59 Dose MF59 Dose MF59 Dose MF59 Dose MF59 Dose MF59 Dose
Antigen Dose1, Day 1, Day 22 none none 75 Dose2 75 Dose2 100 Dose2 100 Dose2
Antigen Dose1, Day 1, Day 22 18 - 64 yrs 65 yrs 18 - 64 yrs 65 yrs 18 - 64 yrs 65 yrs
7.5 µg HA - N 170 170 170 170 170 170
15 µg HA - N 170 170 170 170 170 170
30 µg HA - N 170 170

• 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

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
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H1N1v vaccines in EuropeFocetria 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 gt18y) One year booster Sequential immunization with H1N1v before or after 2008- 2009 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 gt18y) One year booster dose
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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

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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

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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