a 1 Smallpox Vaccine Downselection National Vaccine Advisory Committee February 4, 2003
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Smallpox Vaccine Downselection
National Vaccine Advisory Committee
February 4, 2003
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Joint HHS / DoD Working Group
NVAC DSB
Georges Peter George Poste
Robert Daum Dorothy Margolskee
Stephen Black John Dingerdissen
Richard Whitley Rebecca Devine
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Acambis smallpox vaccines
Vaccine: ACAM1000 ACAM2000
Awarded: September 2000 November 2001
Terms: 20 yr contract Produce stockpile continuous production. in shortest possibleProduce ASAP timeframe
Doses: 54m (originally 40m) 155m
Partner: No Baxter
CDC contract 1 CDC contract 2
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Dryvax®
ACAM1000
ACAMBIS2 x 500 Lfermentor
scale
Warm-base manufacturingto 2020, surge capacity for
US biodefense
54 million dosestockpile USbiodefense
ACAM2000
BAXTER/ACAMBIS
1,200 Lfermentor
scale
155 million dosestockpile USbiodefense
MRC-5 humandiploid cells
Vero cellsSerum- and
animal protein-free
Two contracts, two vaccines
Passage historyDryvaxPool of 3 lots
Plaque purify
ACAM1000Master Virus Seed
Passage 7
ACAM1000Production Virus
SeedPassage 8
ACAM1000Vaccine
Passage 9
ACAM2000ProductionVirus SeedPassage 8
ACAM2000Vaccine
Passage 10
AmplificationPassage 9
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Cloning rationale
> Dryvax® a swarm of virus subpopulations> DNA genome, clonal vaccine will have stable
genotype and phenotype> Consistency of manufacture> Removal of adventitious passenger viruses
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Comparative evaluation of ACAM1000 and Dryvax®
?Lower -IFN BPHrm gene expressionHuman cells
SameReplication, plaque morphology
Cell culture
Same
In progress
Hind III Restriction map
Sequence
Genome
Same
Lower
Same
Same
Same
Lower
Lower
Same or higher
Same
vs. Dryvax®
Gene expression (microarray)Human (ex vivo)
Neurovirulence
Dermovirulence
Antibody responses
Monkey
DermovirulenceRabbit
Neurovirulence
Replication in brain tissue
Antibody, T cell responses
Protection vs. challenge
Mouse
ParameterModel
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Pharmacology-toxicology summary
> ACAM1000 and ACAM2000 have an acceptable preclinical safety and immunogenicity profile
> Both vaccines resemble Dryvax® in their biological characteristics
> ACAM1000 and ACAM2000 have similar biological characteristics
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Regulatory status
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‘Rolling BLA’
21 Aug 02IND BB-IND #10268
ACAM2000R&D initiated 1Dec01
2322 Jan 02IND BB-IND #10253
78 Jan 02Master File BB-MF #10227
ACAM1000R&D initiated 1Oct00
No. amendments
Original submission
DocumentProduct
Clinical trials
Q1 2 3 4 Q1 2 3 4
Phase 1 N=100Phase 2 dose (naïve) N=350 Phase 2 dose (vaccinated) N=350
Phase 3 N=4000
Phase 1 N=100
Phase 2 dose (naïve) N=350 Phase 2 dose (vaccinated) N=350
Phase 3 N=4000
Phase 2 immunology N=90
ACAM1000
ACAM2000
ACAM1000/ 2000
2002 2003
Manufacturingoverview
Cellexpansion
Seed virus Infection
Cell harvest
Celldisruption
(Microfluidizer)
Benzonasedigestion
UltrafiltrationDiafiltration
Dilute todesiredpotency
Fill,lyophilize
ACAM1000 P8ACAM2000 P9
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Current status of manufacture (as of 6-Dec-02)
YesNoDeliverable to NPS
Licensable productClinical trial material
Regulatory status
No. doses
No. lots
1,200 L bioreactor10 layer NCFsScale
FinalPilotProcess
ACAM2000ACAM1000
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ACAM2000 product flow
AcambisMaster Virus Seed
Baxter (Orth)1. Vero cell banks
2. Production Virus Seed3. ACAM2000 crude bulk
(1,200 L)
Acambis(Canton MA) Downstream
processing to final Drugproduct
ChesapeakeBiological
Laboratories (CBL)(Baltimore MD) Fill, lyophilize
Baxter(Bloomington IN)
Label, kit
Precision MedicalProducts
(Denver PA)Bifurcated needles
NationalPharmaceutical
Stockpile
CBLManufacture
diluent
Baxter(Rochester MI)Temp storage
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Current status of manufacture (as of 6-Dec-02)
YesNoDeliverable to NPS
Licensable productClinical trial material
Regulatory status
No. doses
No. lots
1,200 L bioreactor10 layer NCFsScale
FinalPilotProcess
ACAM2000ACAM1000
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ACAM1000 scale-up status
> Limited to PD on cell expansion with no virus work until ACAM2000 manufacture completed in Jan03
> MRC-5 cells grown at 50L scale with adequate cell density
> Successful bead-bead transfer 50L50L> Planned: scale up 50L500L> PD on cell harvest from microcarriers in progress> Some equipment (centrifuge, cell separator) not yet
in place
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Summary
> ACAM1000 and 2000 are equivalent in their preclinical and clinical activities
> ACAM1000 and 2000 are similar to Dryvax® in their biological characteristics
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Summary
> ACAM2000 is far ahead of ACAM1000 with respect to development and manufacturing– ACAM2000
– bulk fermentation completed– manufactured at scale (~8 m doses finished
product/week)– 155 m doses kitted/delivered May03
– ACAM1000 – No bulk fermentation until a) completion of ACAM2000
purification and b) ACAM1000 process development for production at scale (Apr03)
– 54 m doses kitted/delivered Oct03
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Summary
> ACAM2000 has minimal risk– ACAM2000
– bulk fermentation completed– GMP production of finished product (multiple lots)– Clinical proof of principle established with lot produced
at scale
– ACAM1000 – Cell expansion scale up not yet achieved – Virus yields at scale uncertain– No GMP production at scale– Clinical proof of principle established with small-scale
pilot lot
Options for completion of 155 + 54 m (209 m) doses
ACAM2000 155 mdoses
Phase III trial
ACAM2000 54 mdoses
BLA
ACAM1000 54 mdoses
Warm basemanufacturing to
2020
Phase III trial
BLAWarm base
manufacturing to2020
ACAM2000 155 mdoses
Change-over
Option 1
Option 2
Feb04
Jun04
Jun03Apr03
Dec03
Oct03
Apr04
Continuous production of ACAM2000
Baxter (Orth) bulk 155 m doses 54 m doses
Transfer Vero cellbank
In-house production 500 L scale
209 m dose initialstockpile
Warm-base manufacture to 2020
Bridging studyPhase III trial
April 03 Jun03 Jun03
Dec03
Jul03Feb03
Jun04
BLA
Feb04
Risks and benefits
Option 1 (ACAM2000)> Bulk vaccine completed> Seamless completion of 54 m
additional doses using existing process
> Minimal risk> Validation essentially complete> No change-over at Canton and
CBL> One Phase III trial ($40 m)> Full stockpile licensed product
at least 4 mo. earlier
Option 2 (ACAM1000+2000)> No bulk manufactured> MRC-5 scale-up not yet
accomplished> Process development required
for virus production at scale> Risk of delays> New validation program> Change-over at Canton and CBL> Two Phase II trials ($80 m)> Full stockpile licensed product at
least 4 mo. later