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					    DHHS supported influenza cell culture vaccine production facility, Holly Springs, N Carolina




Novartis Vaccines -
Influenza A H1N1v vaccine development
Theodore F Tsai MD MPH
July 23, 2009
                                                                              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
                                                                               H5N1                  H1N1v
   Vaccine           Licensure         Formulation         Indication
                                                                             subclades               Trials
Unadjuvanted, trivalent inactivated vaccine, egg-derived
                                                                                   1 (trial)           +/-
Fluvirin               US                Subunit            4+ years
                                                                          1, 2.2, 2.3 (stockpiled)    MF59

Agrippal         Ex-US/US BLA            Subunit              6m +

Adjuvanted seasonal and prepandemic/pandemic, egg-derived

FLUAD®           Europe, others          Subunit            65+ years

                   Europe, US
AFLUNOV®                              Subunit 7.5 μg        18+ years          1, 2.2 (trials)
                 In development

                    Europe            Subunit 7.5 μg         18+ years                                 +/-
FOCETRIA
               Mock-up pandemic                            (+ 6 months)                               MF59
Cell culture-derived seasonal and pandemic

OPTAFLU         Europe- Seasonal         Subunit            18+ years            2.1 (trial)

Un-named                                                                                               +/-
                  Germany CTA            Subunit           (6+ months)
H1N1v                                                                                                 MF59
                                                                                                                                                                  4
      Multiple potential advantages of MF59 adjuvant in
      pandemic and seasonal influenza vaccines
      MF-59 oil in water emulsion adjuvant                                                                                               GMTs
                                                                                                                               688        585          344
       A component of seasonal influenza vaccine
            Seroprotection rate            Seroconversion rate
        FLUAD* for adults >65 years old, licensed
         97      97                    97       97
100     since 1997              100                                                                                     140    129
                             89                                    89
        • More than 45 million doses distributed




                                                                         HI antibody fold-rise
                                                                                                                                          117
                                                                                                                        120
80                                                       80




                                                                                        Geometric mean ratio (D43/D1)
        • Controlled clinical trial data on >33,000
                                                                                                                        100
          subjects
                                    Seroconversion (%)


60                                    60
        • Ongoing FLUAD - active/placebo controlled                                                                     80
                                                                                                                                                        67
          efficacy trial in 3,000 6-36 month old subjects
40                                                       40                                                             60
        • No safety signals in either the clinical trial
          database or in pharmacovigilance.                                                                             40
20                                                       20
       Adjuvanted vaccine provides higher and                                                                          20

 0
        broader antibody responses
                                 0                                                                                       0
          • Cross-reactive antibody responses against
       Toddlers   Children Adolescents     Toddlers Children   Adolescents                                                    Toddlers   Children   Adolescents
       6-<36 mo    3-<9 y    9-17 y        6-<36 mo  3-<9 y      9-17 y                                                       6-35 mo      3-8 y      9-17 y
            antigenically drifted seasonal strains (n=91)
        (n=134)    (n=91)    (n=89)         (n-131)              (n=89)                                                        (n=134)    (n=91)      (n=89)
        • Broadly cross-reactive responses against                                                    • HI antibody response against an
          the majority of H5N1 subclades
         CHMP benchmarks are for adults                                                               homologous H5N1 Vietnam strain at day 43
        • Allows for antigen sparing                                                                  • Vaccine contained 7.5 µg HA and full MF59
                                                                                                      dose

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

                                              MF59*        0        25%       50%           100%
                                      100



                                      75
                 % HI ≥ 40 (95% CI)




                                                                                                               *Compared to MF59
                                                                                                               content in EMEA-
                                      50                                                                       licensed MF59-
                                                                                                               adjuvanted seasonal
                                                                                                               influenza vaccine

                                      25



                                        0
                                                  3.75                      7.5                         15
                                                                     HA antigen (µg dose)

                                       N    55   55   53       52      51   51 53     52           58   50 59 47
NCT00812019
Keitel W et al
(submitted)
                                                                                              6


       MF59 Clinical Database
       Total number of subjects in controlled clinical studies (as of June 2009)

                               Influenza Studies       Non-influenza         Combined
                                                         Studies
     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               291        235        N/A        N/A      291       235
     underlying medical
     conditions
     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
                                                                             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

                                           Subject age
     Formulation        3 - 17 years      18 - 64 years        >65 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
                                                                                      9

  Fluvirin H1N1v - Pilot clinical trial
  Trial design

                                                Age Group, Number of Subjects
       Vaccine              Vaccination
     Formulation             Schedule          Children    Children       Adults
                                               3 - 8 yrs   9 - 17 yrs   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
                                                                                                                                                            10

 Fluvirin H1N1v – Vaccine registration studies
 Trial design

 Adult & elderly pivotal trial:                          N = 2,380
 Pediatric trial, 3y – 9 years: N = 1,190
                                                                                    MF59 Dose
     Antigen        Dose1,                       none                               75% Dose2                             100% Dose2
      Day 1, Day 22                       18 - 64                                18 - 64                               18 - 64
                                                    ≥65 yrs                               ≥65 yrs                               ≥65 yrs
                                           yrs                                    yrs                                   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 ®
                                                                                    11

  H1N1v vaccines in Europe
  Focetria and Cell derived-vaccines - Trial Overview

             Vaccine may be licensed based on manufacturing data
             2 studies planned
               • 15 µg unadjuvated vs. lower doses, adjuvanted
Focetria       • Separate adult & pediatric studies (6m-17y & >18+y)
H1N1v          • One year booster
             Sequential immunization with H1N1v before or after 2008-
            2009 plain or adjuvanted seasonal TIV



             Leister University pilot trial
               • 15 ug unadjuvanted vs lower doses, adjuvanted, various schedules
Cell           • First subject, first visit - July 23
culture-       • Earliest result - mid-Sep
derived
H1N1v        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

				
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posted:11/6/2011
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