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1

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

14

‘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