1 Introduction to ACAM2000 Smallpox Vaccine David Wonnacott, PhD Senior Vice President of Quality and Regulatory

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Introduction to ACAM2000 Introduction to ACAM2000 Smallpox VaccineSmallpox Vaccine

David Wonnacott, PhDDavid Wonnacott, PhDSenior Vice President of Senior Vice President of Quality and RegulatoryQuality and Regulatory

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Acambis OverviewAcambis Overview

• Acambis develops novel vaccines to prevent and treat Acambis develops novel vaccines to prevent and treat infectious diseasesinfectious diseases

• Acambis locations:Acambis locations:– Cambridge, UK (Head Office)Cambridge, UK (Head Office) –– Canton, MA (manufacturing)Canton, MA (manufacturing)– Cambridge, MA (R&D)Cambridge, MA (R&D) –– Rockville, MD (lyophilization, Rockville, MD (lyophilization,

fill/finish)fill/finish)

• 200+ employees200+ employees

3

““Answering The Call”Answering The Call”

• Critical demand for new and improved Critical demand for new and improved smallpox vaccinesmallpox vaccine

– Commercial manufacturing ceased after Commercial manufacturing ceased after elimination of disease (1970’s)elimination of disease (1970’s)

– Strategic National Stockpile required Strategic National Stockpile required new source of vaccinenew source of vaccine

• ACAM2000 is uniqueACAM2000 is unique– Needed to establish safety and efficacy Needed to establish safety and efficacy

in absence of disease in absence of disease – Highly targeted use managed by Highly targeted use managed by

government agenciesgovernment agencies

4

ManufacturingManufacturing

Today’s BioreactorToday’s BioreactorACAM2000, 2001 - ongoingACAM2000, 2001 - ongoing

Original BioreactorOriginal BioreactorCalf skin vaccines, begun in 1805Calf skin vaccines, begun in 1805

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ACAM2000ACAM2000 DryvaxDryvax®®

Clonal, homogeneousClonal, homogeneous(< 0.4% genome changes)(< 0.4% genome changes)

Uncloned, heterogeneousUncloned, heterogeneous

Produced in cell culture Produced in cell culture without bovine serumwithout bovine serum

Produced in calf skinProduced in calf skin

Enhanced, Modern cGMP Enhanced, Modern cGMP Purification MethodPurification Method

Purified to standards of the Purified to standards of the time (1970’s)time (1970’s)

Tested at current requirements, Tested at current requirements, negative for adventitious negative for adventitious virusesviruses

Tested to release standards Tested to release standards of the time (1970’s)of the time (1970’s)

Less neurovirulentLess neurovirulent(mice, monkeys)(mice, monkeys)

Moderate neurovirulence Moderate neurovirulence (mice, monkeys)(mice, monkeys)

Large scale production and Large scale production and surge capacitysurge capacity

Original production methodsOriginal production methods

Differences from Currently Licensed Differences from Currently Licensed Smallpox VaccineSmallpox Vaccine

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192.5 million doses192.5 million dosesdelivered to SNS*delivered to SNS*

Parallel Clinical Development and Manufacturing Parallel Clinical Development and Manufacturing Timeline for Smallpox Vaccine (ACAM2000)Timeline for Smallpox Vaccine (ACAM2000)

9/11 9/11 and 10/01and 10/01

8/028/02

Clinical trial programClinical trial program(Phase I - III)(Phase I - III)

CDC contractCDC contractawarded toawarded to

AcambisAcambis

11/0111/01

INDINDfiledfiled

10/0210/02

12/0212/02

2/052/05 8/068/06

12/0612/06

Terrorist Terrorist and anthraxand anthrax

attacksattacks

BLA filedBLA filed

12/0412/04

Fast TrackFast TrackDesignationDesignation

* SNS – Strategic National Stockpile* SNS – Strategic National Stockpile

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Acambis PresentationsAcambis Presentations

Smallpox Smallpox Historical OverviewHistorical Overview

John Neff, MDJohn Neff, MDSeattle Children’s Hospital and Seattle Children’s Hospital and Regional Medical CenterRegional Medical Center

ACAM2000 ACAM2000 Development ProgramDevelopment Program

Thomas P. Monath, MDThomas P. Monath, MDFormer Acambis Chief Scientific OfficerFormer Acambis Chief Scientific Officer

Smallpox Smallpox Vaccine-Related Vaccine-Related MyocarditisMyocarditis

Jay W. Mason, MDJay W. Mason, MDProf of Medicine, Former Chief of Cardiology, Prof of Medicine, Former Chief of Cardiology, University of UtahUniversity of UtahProf of Medicine, Former Chair of Medicine, Prof of Medicine, Former Chair of Medicine, University of KentuckyUniversity of Kentucky

Risk Management Risk Management ProgramProgram

Michael Watson, MD, PhDMichael Watson, MD, PhDExecutive Vice President of Executive Vice President of Research and DevelopmentResearch and Development

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History of Smallpox Disease, History of Smallpox Disease, Vaccination, and EradicationVaccination, and Eradication

John Neff, MDJohn Neff, MDSeattle Children’s Hospital and Seattle Children’s Hospital and

Regional Medical CenterRegional Medical Center

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Topics to be CoveredTopics to be Covered

• History of SmallpoxHistory of Smallpox– Control, eradication, and potential Control, eradication, and potential

for bioterrorism usefor bioterrorism use

• Smallpox VaccinationSmallpox Vaccination– Development, protection, adverse eventsDevelopment, protection, adverse events

• Description of SmallpoxDescription of Smallpox– Clinical types and expected mortalityClinical types and expected mortality

• ConclusionsConclusions

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History of Smallpox History of Smallpox

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Overview of SmallpoxOverview of Smallpox

• First appeared possibly 1100 BCFirst appeared possibly 1100 BC– Origin was probably from closely Origin was probably from closely

related animal pox viruses of the related animal pox viruses of the orthopox virus grouporthopox virus group

• Smallpox became worldwide and endemic Smallpox became worldwide and endemic throughout Europe and caused pandemics throughout Europe and caused pandemics with high mortalities in the Americaswith high mortalities in the Americas

• Responsible for estimated 300 million Responsible for estimated 300 million deaths in 20deaths in 20thth century century

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Control of SmallpoxControl of Smallpox

• Variolation developed in Far East and introduced to EuropeVariolation developed in Far East and introduced to Europe

• 1796:1796: First vaccinia-based vaccination by Edward JennerFirst vaccinia-based vaccination by Edward Jenner

• 1967: 1967: Enhanced WHO eradication programEnhanced WHO eradication program

• 1972: 1972: Vaccination ended in USVaccination ended in US

• 1977:1977: Last natural case of smallpox (Somalia)Last natural case of smallpox (Somalia)

• 1978:1978: Last death/case of smallpox, lab acquired – air Last death/case of smallpox, lab acquired – air vent vent system, Janet Parker in Birmingham, England system, Janet Parker in Birmingham, England

• 1980:1980: WHO declared smallpox eradicatedWHO declared smallpox eradicated

• 1984:1984: Official repositories of variola designated as CDCOfficial repositories of variola designated as CDCin Atlanta, GA and Vector in Novosibirsk, Russiain Atlanta, GA and Vector in Novosibirsk, Russia

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Smallpox – Current ConcernsSmallpox – Current Concerns

• Soviet government bioweapons programSoviet government bioweapons program– Aimed to produce smallpox in large quantities Aimed to produce smallpox in large quantities

and adapt it for use in bombs and ICBMsand adapt it for use in bombs and ICBMs– Industrial capacity capable of producing many Industrial capacity capable of producing many

tons of smallpox virus annuallytons of smallpox virus annually

• Stocks in official repositories may not be secureStocks in official repositories may not be secure– With break-up of Soviet Union, security With break-up of Soviet Union, security

at Vector was poorat Vector was poor

• Risk that rogue states did not destroy stocksRisk that rogue states did not destroy stocks– Could be used for bioterrorism purposesCould be used for bioterrorism purposes

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Smallpox VaccinationSmallpox Vaccination

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History of Vaccinia as Smallpox VaccineHistory of Vaccinia as Smallpox Vaccine

• Vaccinia obtained from animals, Vaccinia obtained from animals, presumably cows or horsespresumably cows or horses

• Member of Orthopox familyMember of Orthopox family

• Related to both cowpox and variolaRelated to both cowpox and variola

• Initially propagated from person to personInitially propagated from person to person

• The coordinated use of two standardized The coordinated use of two standardized vaccinia strains, Lister and NYCBH, were vaccinia strains, Lister and NYCBH, were responsible for eradicating smallpox responsible for eradicating smallpox worldwide by 1980worldwide by 1980

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Evidence of ProtectionEvidence of Protection

• Cutaneous Reaction (dermal take)Cutaneous Reaction (dermal take)– ““Major reaction” correlates with Major reaction” correlates with

• Protection against smallpox Protection against smallpox • Development or presence of neutralizing Development or presence of neutralizing

antibodies and T cellsantibodies and T cells

• Neutralizing Antibodies Neutralizing Antibodies – Neutralizing antibodies correlate with protection Neutralizing antibodies correlate with protection

against smallpox in humansagainst smallpox in humans– Mice and monkeys with neutralizing antibodies and T Mice and monkeys with neutralizing antibodies and T

cell depletion are protectedcell depletion are protected– Passive immunization provides some protectionPassive immunization provides some protection

• T cells may also play an important roleT cells may also play an important role

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Protection from VaccinationProtection from Vaccination

• Complete protection for three to five yearsComplete protection for three to five years

• Partial protection for up to 25 yearsPartial protection for up to 25 years

• Perhaps long-term protection against deathPerhaps long-term protection against death

Case Fatality Rate of Smallpox After Importations into Case Fatality Rate of Smallpox After Importations into Western Countries During the Period 1950-1971Western Countries During the Period 1950-1971

Successfully VaccinatedSuccessfully Vaccinated Case Fatality RateCase Fatality Rate

0-10 years before exposure0-10 years before exposure 1.4%1.4%

11-20 years before exposure11-20 years before exposure 7%7%

> 20 years before exposure> 20 years before exposure 11%11%

Only after the exposureOnly after the exposure 29%29%

NeverNever 52%52%

Fenner F et al. Smallpox and its Eradication, pp53Fenner F et al. Smallpox and its Eradication, pp53

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Historic Understanding of Adverse Events: Data Historic Understanding of Adverse Events: Data from US Routine Vaccination Programs in 1960sfrom US Routine Vaccination Programs in 1960s

ComplicationComplication # of cases# of cases CommentsComments

Progressive Progressive VacciniaVaccinia

1-7 cases per 1-7 cases per 1,000,000 vaccinations1,000,000 vaccinations

• Mortality: 25-60%Mortality: 25-60%

• Susceptibility Susceptibility

• CD4 T cell count < 200/mmCD4 T cell count < 200/mm22

Eczema Eczema VaccinatumVaccinatum

2-4 cases per 100,000 2-4 cases per 100,000 primary vaccinationsprimary vaccinations

• ~ 1% mortality~ 1% mortality

• 20-30% will be in contacts20-30% will be in contacts

Post Vaccinal Post Vaccinal EncephalitisEncephalitis

1-2 per 100,000 primary 1-2 per 100,000 primary vaccinationsvaccinations

• 1-10% mortality or significant 1-10% mortality or significant neurological impairmentneurological impairment

Contact VacciniaContact Vaccinia 2-6 cases per 100,000 2-6 cases per 100,000 primary vaccinationsprimary vaccinations

• One-third of cases in children One-third of cases in children with history of eczemawith history of eczema

• Required close body contactRequired close body contact

Accidental Accidental InfectionsInfections

1-6 cases per 1,0001-6 cases per 1,000 • No mortalityNo mortality

• Rare ocular impairmentRare ocular impairment

Erythematous Erythematous ReactionsReactions

Occurs up to 1 per 100 Occurs up to 1 per 100 primary vaccinationsprimary vaccinations

• Very mildVery mild

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Clinical Description of SmallpoxClinical Description of Smallpox

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SmallpoxSmallpox

CommunicabilityCommunicability DayDay Symptoms & PathogenesisSymptoms & Pathogenesis

NotNotContagiousContagious

1-31-3NoNo

SymptomsSymptoms

virus intro’d to resp tractvirus intro’d to resp tract

4-54-5 appears in lymph nodesappears in lymph nodes

6-116-11 replicates in lymph systemreplicates in lymph system

12-1312-13 FirstFirstSymptomsSymptoms

Viremia, fever, backache, Viremia, fever, backache, headache, nausea, malaiseheadache, nausea, malaise

ContagiousContagious1414

1515

RashRash

maculesmacules

VeryVeryContagiousContagious

16-1816-18 papulespapules

19-2019-20 vesiclesvesicles

ContagiousContagious21-2421-24 pustulespustules

2525

scabsscabsMinimally Minimally ContagiousContagious 26-3026-30

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Progression of SmallpoxProgression of Smallpox

Source: CDC

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Clinical Features of SmallpoxClinical Features of Smallpox

• DiscreteDiscrete

• ConfluentConfluent

• FlatFlat

• HemorrhagicHemorrhagic

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Smallpox – DiscreteSmallpox – Discrete

Areas of normal skin between Areas of normal skin between pustules even on facepustules even on face

Source: CDC

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Smallpox – Confluent Smallpox – Confluent

Confluent rash on face and forearmsConfluent rash on face and forearms

Source: CDC

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Smallpox – Flat Smallpox – Flat

Pustules confluent or Pustules confluent or semiconfluent – appear flatsemiconfluent – appear flat

Source: CDCSource: CDC

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Smallpox – HemorrhagicSmallpox – Hemorrhagic

Widespread hemorrhage into skin, Widespread hemorrhage into skin, early and late forms, 98% case fatalityearly and late forms, 98% case fatality

Source: CDC

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Smallpox MortalitySmallpox Mortality

Mortality from infection with Mortality from infection with variola major in unvaccinated variola major in unvaccinated individuals can be up to 50% individuals can be up to 50%

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ConclusionsConclusions

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• Smallpox is a devastating disease with a Smallpox is a devastating disease with a very high mortality rate in the non-immunevery high mortality rate in the non-immune

• Vaccination historically associated with Vaccination historically associated with significant adverse eventssignificant adverse events

• Populations are immunologically vulnerable Populations are immunologically vulnerable following eradication following eradication and end of vaccination programs and end of vaccination programs

• In the United States, few people have been In the United States, few people have been vaccinated in 34 yearsvaccinated in 34 years

Continued

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Conclusions Conclusions (Continued)

• As long as variola virus exists anywhere, As long as variola virus exists anywhere, there will be the need to have a smallpox there will be the need to have a smallpox vaccine available in the event of a vaccine available in the event of a bioterrorism threat or laboratory accidentbioterrorism threat or laboratory accident

• It is in our best interest to have a modern It is in our best interest to have a modern smallpox vaccine availablesmallpox vaccine available

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ACAM2000 Smallpox Vaccine ACAM2000 Smallpox Vaccine Development ProgramDevelopment Program

Thomas P. Monath, MDThomas P. Monath, MDFormer Acambis Chief Scientific OfficerFormer Acambis Chief Scientific Officer

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Vaccine Development Goals MetVaccine Development Goals Met

• Purified clone derived from DryvaxPurified clone derived from Dryvax®® (NYCBH vaccinia strain)(NYCBH vaccinia strain)

• Well characterized seed lot free of adventitious agents Well characterized seed lot free of adventitious agents

• GMP manufacturing in cell culture (Vero) using GMP manufacturing in cell culture (Vero) using modern standardsmodern standards

• Meets all release specifications including potency Meets all release specifications including potency ≥ 10≥ 1088 PFU/mL PFU/mL

• Clinical safety similar to or better than DryvaxClinical safety similar to or better than Dryvax®®

• Demonstrated clinical efficacy (some differences Demonstrated clinical efficacy (some differences from Dryvaxfrom Dryvax®®))

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Indication/UseIndication/Use

• Vaccination with ACAM2000 is indicated Vaccination with ACAM2000 is indicated for protection of persons determined to be for protection of persons determined to be at high risk for smallpox infectionat high risk for smallpox infection

• Not for routine vaccination of general Not for routine vaccination of general populationpopulation

• Stored and controlled by Strategic Stored and controlled by Strategic National Stockpile (SNS)National Stockpile (SNS)

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• IntroductionIntroduction

• Nonclinical dataNonclinical data

• Clinical dataClinical data– SafetySafety– EfficacyEfficacy


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Nonclinical SummaryNonclinical Summary

• Toxicology studies in mice and cynomolgus Toxicology studies in mice and cynomolgus macaques inoculated macaques inoculated IC show ACAM2000 less neurovirulent than IC show ACAM2000 less neurovirulent than DryvaxDryvax®®

• ACAM2000 and DryvaxACAM2000 and Dryvax®® have similar have similar immunogenicity in mice and monkeysimmunogenicity in mice and monkeys

• Both vaccines protect mice and cynomolgus Both vaccines protect mice and cynomolgus macaques against lethal homologous and macaques against lethal homologous and heterologous poxvirus challengeheterologous poxvirus challenge

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ACAM2000 Is Less Neurovirulent than DryvaxACAM2000 Is Less Neurovirulent than Dryvax®® 3-4 Day-old Mice Inoculated IC, n=32/Group3-4 Day-old Mice Inoculated IC, n=32/Group

0 3 6 9 12 15 18 210

20

40

60

80

100

ACAM2000 VV02-007

Dryvax

Neg Control

Day of Death

% S

urvi

ving

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ACAM2000 and DryvaxACAM2000 and Dryvax®® Elicit Similar Immune Elicit Similar Immune Responses and Protect Cynomolgus Monkeys against Responses and Protect Cynomolgus Monkeys against Lethal Monkeypox Challenge (3.8 x 10Lethal Monkeypox Challenge (3.8 x 1077 PFU IV) PFU IV)

ParameterParameterACAM2000ACAM2000

(n=8)(n=8)DryvaxDryvax®®

(n=8)(n=8)ControlControl

(n=8)(n=8)

ImmunizationImmunization

Pock response Pock response rate (mm, D10)rate (mm, D10)

8/8 (11.0)8/8 (11.0) 8/8 (11.3)8/8 (11.3) 0/8 (-)0/8 (-)

N antibodyN antibody(GMT, D30)(GMT, D30)

160160 174174 <10<10

ChallengeChallenge

Pox lesionsPox lesions None None

NoneNone >100 per region>100 per region

Temp. Temp. (2-3 days post challenge)(2-3 days post challenge)

NormalNormal NormalNormal >103° C>103° C

Virus replicationVirus replication NoneNone + throat in 3/8+ throat in 3/8 ++plasma (6/8)++plasma (6/8)

++PBMC (6/8)++PBMC (6/8)

+++throat (8/8)+++throat (8/8)

DeathDeath NoneNone NoneNone 8/88/8

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39

ACAM2000 Clinical StudiesACAM2000 Clinical Studies

PhasePhase ProtocolProtocol StatusStatus

ObjectivesObjectives

SafetySafetyCut. Cut.

responseresponseAnti-Anti-bodybody

DoseDoseresp.resp.

Lot Lot consist.consist.

TTcellscells

Viremia, Viremia, sheddingshedding

Nonspec Nonspec serologyserology

11 H-400-008H-400-008 NaïveNaïve

11 H-400-002H-400-002 NaïveNaïve

22 H-400-005H-400-005 NaïveNaïve

22 H-400-003H-400-003 PreviouslyPreviouslyVaccinatedVaccinated

33 H-400-009H-400-009 NaïveNaïve

33 H-400-012H-400-012 PreviouslyPreviouslyVaccinatedVaccinated

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Subjects Evaluated for SafetySubjects Evaluated for Safety

ACAM2000ACAM2000 DryvaxDryvax®®

TotalTotal

Vaccinia- Vaccinia- NaïveNaïve

nn

PreviouslyPreviouslyVaccinatedVaccinated

nn

Vaccinia- Vaccinia- Naïve Naïve

nn

PreviouslyPreviouslyVaccinatedVaccinated

nn

Phase IPhase I 130130 00 3030 00 160160

Phase IIPhase II 304304 305305 4949 5252 710710

Phase III*Phase III* 873873 13711371 289289 448448 29812981

Sub-totalSub-total 13071307 16761676 368368 500500

TotalTotal 29832983 868868 38513851

** Phase III study enrollment curtailed due to myocarditis AEs. Phase III study enrollment curtailed due to myocarditis AEs. Planned enrollment 2040 ACAM2000 and 680 DryvaxPlanned enrollment 2040 ACAM2000 and 680 Dryvax®®

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Phase III Subject DispositionPhase III Subject DispositionSafety PopulationSafety Population

H-400-009 H-400-009 (Vaccinia-Naïve)(Vaccinia-Naïve)

H-400-012 H-400-012 (Previously Vaccinated)(Previously Vaccinated)

ACAM2000ACAM2000n=873n=873

DryvaxDryvax®® n=289n=289

ACAM2000ACAM2000n=1371n=1371


VaccinatedVaccinatedn (%)n (%)

873873(100%)(100%)

289289(100%)(100%)

13711371(100%)(100%)

448448(100%)(100%)

CompletedCompletedn (%)n (%)

863863(99%)(99%)

287287(99%)(99%)

13621362(99%)(99%)

442442(99%)(99%)

WithdrewWithdrewn (%)n (%)

1010(1%)(1%)

22(<1%)(<1%)

99(<1%)(<1%)

66(1%)(1%)

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Phase III DemographicsPhase III DemographicsSafety PopulationSafety Population

H-400-009 H-400-009 (Vaccinia-Naïve)(Vaccinia-Naïve)

H-400-012 H-400-012 (Previously Vaccinated)(Previously Vaccinated)

ACAM2000ACAM2000n=873n=873


ACAM2000ACAM2000n=1371n=1371


AgeAge(yr, mean)(yr, mean) 2323 2323 48.948.9 49.249.2

MaleMale 66%66% 63%63% 50%50% 48%48%

CaucasianCaucasian 76%76% 71%71% 78%78% 78%78%

African-African-AmericanAmerican 11%11% 14%14% 10%10% 11%11%

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Common Adverse EventsCommon Adverse Events

• Expected AEs known to be associated Expected AEs known to be associated with smallpox vaccinations with smallpox vaccinations

– Inoculation site reactions, Inoculation site reactions, lymphadenitis, feverishness, lymphadenitis, feverishness, chills, fatigue, malaise, myalgia chills, fatigue, malaise, myalgia

• The incidence of these AEs was higher The incidence of these AEs was higher for Dryvaxfor Dryvax®® than ACAM2000 than ACAM2000

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Solicited Adverse Events Occurring in ≥10% Solicited Adverse Events Occurring in ≥10% of Subjects by Treatment Group, Phase IIIof Subjects by Treatment Group, Phase III

Vaccinia-NaïveVaccinia-Naïve Previously VaccinatedPreviously Vaccinated

MedDRA Preferred TermMedDRA Preferred Term

ACAM 2000ACAM 2000(n=873)(n=873)

%%

DryvaxDryvax®®

(n=289)(n=289)%% p-valuep-value

ACAM 2000ACAM 2000(n=1371)(n=1371)

%%

DryvaxDryvax®®

(n=448)(n=448)%% p-valuep-value

At least 1 AEAt least 1 AE 9999 100100 0.4660.466 9797 9999 0.0120.012

Injection site pruritusInjection site pruritus 9292 9696 0.0320.032 8282 9393 <0.001<0.001

Injection site erythemaInjection site erythema 7474 7979 0.0980.098 6161 7272 <0.001<0.001

Injection site painInjection site pain 6767 7272 0.0950.095 3737 4747 <0.001<0.001

Lymph node painLymph node pain 5757 6969 <0.001<0.001 1919 2727 <0.001<0.001

HeadacheHeadache 5050 5252 0.4980.498 3232 3737 0.0490.049

FatigueFatigue 4848 5656 0.0350.035 3434 4141 0.0090.009

Injection site swellingInjection site swelling 4848 5757 0.0100.010 2828 4242 <0.001<0.001

MyalgiaMyalgia 4646 5151 0.1970.197 2727 3333 0.0220.022

MalaiseMalaise 3737 4242 0.1630.163 2828 3333 0.0480.048

Feeling hotFeeling hot 3232 3434 0.5610.561 2020 2525 0.0110.011

ErythemaErythema 2222 2424 0.4640.464 2424 2424 1.0001.000

RigorsRigors 2121 2323 0.5640.564 1212 1717 0.0170.017

NauseaNausea 1919 2222 0.2730.273 1010 1414 0.0390.039

DiarrheaDiarrhea 1616 1212 0.0590.059 1212 1717 0.0030.003

Exercise tolerance decreasedExercise tolerance decreased 1111 1212 0.6710.671 88 1111 0.0250.025

RashRash 1111 1010 0.9130.913 66 66 0.6470.647

LymphadenopathyLymphadenopathy 88 1212 0.0600.060 66 66 0.5630.563

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Serious Adverse Events – All StudiesSerious Adverse Events – All Studies

Vaccinia-Naïve Previously VaccinatedPreviously Vaccinated

ACAM2000ACAM2000(n=1307)(n=1307)

DryvaxDryvax

(n=368)(n=368)ACAM2000ACAM2000

(n=1676)(n=1676)DryvaxDryvax

(n=500)(n=500)

DeathsDeaths 00 00 00 00

At least 1 SAEAt least 1 SAE 13 (1%)13 (1%) 4 (1%)4 (1%) 6 (<1%)6 (<1%) 3 (1%)3 (1%)

Myocarditis / myopericarditisMyocarditis / myopericarditis 7 (0.54%)7 (0.54%) 3 (0.82%)3 (0.82%) 00 00

Atrial fibrillationAtrial fibrillation 00 00 1 (<1%)1 (<1%) 00

Coronary artery diseaseCoronary artery disease 00 00 00 1 (<1%)1 (<1%)

Chest discomfortChest discomfort 00 00 1 (<1%)1 (<1%) 00

Chest painChest pain 00 00 1 (<1%)1 (<1%) 00

HypersensitivityHypersensitivity 00 00 00 1 (<1%)1 (<1%)

AppendicitisAppendicitis 1 (<1%)1 (<1%) 00 1 (<1%)1 (<1%) 00

Generalized vaccinia (‘cowpox’)Generalized vaccinia (‘cowpox’) 00 00 00 1 (<1%)1 (<1%)

HIV test positive subject vaccinatedHIV test positive subject vaccinated 00 00 1(<1%)1(<1%) 00

ConvulsionsConvulsions 1 (<1%)1 (<1%) 00 00 00

Pregnancy during on-study phasePregnancy during on-study phase 4 (<1%)4 (<1%) 00 1 (<1%)1 (<1%) 00

UrticariaUrticaria 00 1 (<1%)1 (<1%) 00 00

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MyocarditisMyocarditis

• Prospective case ascertainment Phase I Prospective case ascertainment Phase I (H-400-002) and Phase III(H-400-002) and Phase III

– ECGs at screening, Day 10 and 21 (Phase III) ECGs at screening, Day 10 and 21 (Phase III) or screening and Day 15 (Phase I)or screening and Day 15 (Phase I)

– Troponin I and/or CK-MB at screening and Troponin I and/or CK-MB at screening and Day 10 (Phase III) or Day 15 (Phase I)Day 10 (Phase III) or Day 15 (Phase I)

– Provoked cardiac AEs (clinic visits, diaries)Provoked cardiac AEs (clinic visits, diaries)

• Myocarditis seen only in vaccinia-naïve subjectsMyocarditis seen only in vaccinia-naïve subjects

• Previous under-reporting based on passive Previous under-reporting based on passive surveillance and symptomatic cases onlysurveillance and symptomatic cases only

47

Myocarditis – Phase I (H-400-002) and Phase III Myocarditis – Phase I (H-400-002) and Phase III (Vaccinia-naïve Subjects, Standardized Case (Vaccinia-naïve Subjects, Standardized Case Ascertainment)Ascertainment)

ACAM2000ACAM2000n=903n=903

DryvaxDryvax®®

n=319n=319

MyocarditisMyocarditis 6 cases (6.6/1000)6 cases (6.6/1000)

2 symptomatic2 symptomatic

1 hospitalized1 hospitalized

3 cases (9.4/1000)3 cases (9.4/1000)

1 symptomatic1 symptomatic

1 hospitalized1 hospitalized

Follow-upFollow-up 6/6 resolved6/6 resolved 2/3 resolved2/3 resolved

1 with ↓ LVEF1 with ↓ LVEF

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49

Vaccine EfficacyVaccine Efficacy

• Efficacy cannot be demonstrated in disease setting due Efficacy cannot be demonstrated in disease setting due to eradication of smallpoxto eradication of smallpox

• Cutaneous ResponseCutaneous Response is a generally accepted surrogate is a generally accepted surrogate of protection (WHO, ACIP)of protection (WHO, ACIP)

• Neutralizing AntibodiesNeutralizing Antibodies are a correlate of protection are a correlate of protection– May be more accurate reflection of vaccine May be more accurate reflection of vaccine

effectiveness in previously vaccinated subjects with effectiveness in previously vaccinated subjects with modified ‘takes’ modified ‘takes’

– Historical data suggest relatively low titers Historical data suggest relatively low titers are protectiveare protective• Mack et al., 1972 (protective titer >1:32)Mack et al., 1972 (protective titer >1:32)• Sarkar et al., 1975 (protective titer >1:20)Sarkar et al., 1975 (protective titer >1:20)

50

Phase III Trials Efficacy AnalysesPhase III Trials Efficacy Analyses

Co-PrimaryCo-Primary Statistical MethodStatistical Method SecondarySecondary

1.1. Cutaneous Cutaneous Response Response RateRate

Non-inferiority Non-inferiority

• Exclude margin of Exclude margin of superiority of Dryvaxsuperiority of Dryvax®® >5% (naïve) or >10% >5% (naïve) or >10% (prev. vacc.)(prev. vacc.)

• Covariate analyses Covariate analyses (baseline immunity, (baseline immunity, H-400-012)H-400-012)

2.2. GMTGMT Non-inferiorityNon-inferiority

• Ratio of Ratio of ACAM2000:DryvaxACAM2000:Dryvax®® GMT at least 0.5 GMT at least 0.5 (log(log1010 -0.301) -0.301)

• Covariate analyses Covariate analyses (baseline immunity, (baseline immunity, H-400-012)H-400-012)

• Titer freq. distributionTiter freq. distribution

• Fold-increase in PRNTFold-increase in PRNT

• Seroconversion ratesSeroconversion rates

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Phase III Endpoint: Cutaneous Response Phase III Endpoint: Cutaneous Response

Vaccinia-NaïveVaccinia-Naïve(Study H-400-009)(Study H-400-009)

Previously VaccinatedPreviously Vaccinated(Study H-400-012)(Study H-400-012)

ACAM 2000ACAM 2000n=776n=776

DryvaxDryvax®®

n=257n=257ACAM 2000ACAM 2000

n=1189n=1189DryvaxDryvax®®

n=388n=388

Positive n (%)Positive n (%) 747 (96%)747 (96%) 255 (99%)255 (99%) 998 (84%)998 (84%) 381 (98%)381 (98%)

97.5% CI97.5% CI(Criteria)(Criteria)

-4.67-4.67(> -5.0%, lower bound (> -5.0%, lower bound of difference in rates)of difference in rates)

-17-17(> -10.0% , lower bound (> -10.0% , lower bound

of difference in rates)of difference in rates)

Non-inferiority Non-inferiority Endpoint met?Endpoint met? YesYes NoNo

• ACAM2000 non-inferior to DryvaxACAM2000 non-inferior to Dryvax®® in vaccinia-naïve in vaccinia-naïve subjectssubjects

• ACAM2000 has lower cutaneous response rate than ACAM2000 has lower cutaneous response rate than DryvaxDryvax®® in previously vaccinated subjects in previously vaccinated subjects

52

Cutaneous Response RatesCutaneous Response RatesPreviously Vaccinated (Phase III), Adjusted for Previously Vaccinated (Phase III), Adjusted for Baseline Antibody Titer (Antibody Evaluable Population)Baseline Antibody Titer (Antibody Evaluable Population)

• Subjects without detectable residual immunity have high Subjects without detectable residual immunity have high vaccination success rate to ACAM2000 (94%)vaccination success rate to ACAM2000 (94%)

• Higher sensitivity to interference by residual immunity Higher sensitivity to interference by residual immunity reflects relative attenuation of ACAM2000 vs. Dryvaxreflects relative attenuation of ACAM2000 vs. Dryvax®®

Baseline TiterBaseline Titer StatisticStatistic

Treatment GroupTreatment Group

ACAM2000ACAM2000(n=706)(n=706)

DryvaxDryvax

(n=364)(n=364)

<1:10<1:10

Cutaneous Cutaneous ResponseResponse

151/161 (94%)151/161 (94%) 86/88 (98%)86/88 (98%)

1:10 – 1:201:10 – 1:20 158/186 (85%)158/186 (85%) 107/108 (99%)107/108 (99%)

1:40 – 1:801:40 – 1:80 168/199 (84%)168/199 (84%) 93/94 (99%)93/94 (99%)

1:1601:160 116/160 (73%)116/160 (73%) 72/74 (97%)72/74 (97%)

53

Neutralizing Antibody Fold-IncreaseNeutralizing Antibody Fold-IncreasePreviously Vaccinated (Phase III), Adjusted for Previously Vaccinated (Phase III), Adjusted for Baseline Antibody Titer (Antibody Evaluable Population)Baseline Antibody Titer (Antibody Evaluable Population)

Baseline TiterBaseline Titer StatisticStatistic

Treatment GroupTreatment Group

ACAM2000ACAM2000(n=706)(n=706)

DryvaxDryvax

(n=364)(n=364)

<1:10<1:10

Fold-Increase Fold-Increase (Geometric (Geometric Mean Titer)Mean Titer)

29.629.6 36.436.4

1:10 – 1:201:10 – 1:20 13.313.3 23.823.8

1:40 – 1:801:40 – 1:80 5.95.9 10.910.9

1:1601:160 2.22.2 4.84.8

54

Phase III Endpoint: Neutralizing AntibodyPhase III Endpoint: Neutralizing Antibody

Vaccinia-NaïveVaccinia-Naïve(Study H-400-009)(Study H-400-009)

Previously VaccinatedPreviously Vaccinated(Study H-400-012)(Study H-400-012)

ACAM 2000ACAM 2000n=565n=565

DryvaxDryvax®®

n=190n=190ACAM 2000ACAM 2000

n=734n=734DryvaxDryvax®®

n=376n=376

GMTGMT 166166 255255 286286 445445

97.5% CI97.5% CI(Criteria)(Criteria)

-0.307-0.307(≥ -0.301*)(≥ -0.301*)

-0.275-0.275(≥ -0.301*)(≥ -0.301*)

Non-inferiority Non-inferiority Endpoint met?Endpoint met? NoNo YesYes

* lower bound on difference in mean log* lower bound on difference in mean log1010 GMT GMT

• ~ 1.5-fold lower GMT following ACAM2000 vs. Dryvax~ 1.5-fold lower GMT following ACAM2000 vs. Dryvax®®

• Non-inferiority endpoint narrowly missed in primary Non-inferiority endpoint narrowly missed in primary vaccination, met in previously vaccinated subjectsvaccination, met in previously vaccinated subjects

55

>90% of Subjects Have Antibody Titers >90% of Subjects Have Antibody Titers Greater than Historical Protective LevelGreater than Historical Protective Level

56

Categorical and Median T cell responsesCategorical and Median T cell responsesNaïve Subjects (H-400-002)Naïve Subjects (H-400-002)

DryvaxDryvax®® (n=30) (n=30)ACAM2000 (n=30)ACAM2000 (n=30)

86.7%

100.0% 96.7%

86.7%

73.3%

90.0%

Cytotoxic TCytotoxic TLymphocytic (LU)Lymphocytic (LU)

gamma-IFN ELISPOTgamma-IFN ELISPOT(SFC/10(SFC/1066))

LymphoproliferationLymphoproliferation(SI)(SI)

medianmedian 15.95 12.5 296 264 25.0 23.1

57

T cell (T cell (-IFN-ELISPOT) Responses (H-400-002)-IFN-ELISPOT) Responses (H-400-002)

Positive response >20 spot-forming cells/10Positive response >20 spot-forming cells/1066

500

0

1500

1000

Sp

ot

form

ing

cel

ls/m

illi

on

ACAM2000 Dryvax®

58


• Modern processes and QC methods used in Modern processes and QC methods used in large-scale manufacturing of ACAM2000large-scale manufacturing of ACAM2000

– Safety assurance greater than production on calf skin Safety assurance greater than production on calf skin (potential for adventitious agents)(potential for adventitious agents)

– 75 lots,192.5M doses deposited in SNS 75 lots,192.5M doses deposited in SNS

• Purified clonal vaccine, less neurovirulent in animal modelsPurified clonal vaccine, less neurovirulent in animal models

• Immunogenic and protective against lethal pox Immunogenic and protective against lethal pox in 4 animal models, 2 speciesin 4 animal models, 2 species

• Clinical data demonstrate safety and tolerability equivalent Clinical data demonstrate safety and tolerability equivalent to or better than Dryvaxto or better than Dryvax®®

– Vaccinia-associated myocarditis incidence Vaccinia-associated myocarditis incidence approximately 1 in 150approximately 1 in 150

59

Conclusions Conclusions (Continuing)

• Primary indicators of immunity support ACAM2000 Primary indicators of immunity support ACAM2000 efficacy in naïve subjectsefficacy in naïve subjects

– Cutaneous ResponseCutaneous Response– 96% ‘take’ rate96% ‘take’ rate– Non-inferior to DryvaxNon-inferior to Dryvax®®

– Neutralizing AntibodyNeutralizing Antibody– High GMT (166)High GMT (166)– >90% with neutralizing antibody titers above >90% with neutralizing antibody titers above

putative protective level of 1:32putative protective level of 1:32– Narrowly missed statistical non-inferiority endpoint Narrowly missed statistical non-inferiority endpoint

in naïve subjects (-.307 vs -.301)in naïve subjects (-.307 vs -.301)

– Robust T cell responses similar to DryvaxRobust T cell responses similar to Dryvax®®

– Important for immunological memoryImportant for immunological memory

60

Conclusions Conclusions (Continuing)

• Primary indicators of immunity support ACAM2000 Primary indicators of immunity support ACAM2000 efficacy in previously-vaccinatedefficacy in previously-vaccinated

– Neutralizing AntibodyNeutralizing Antibody– May be better measure of vaccine effectiveness May be better measure of vaccine effectiveness

due to modified ‘takes’due to modified ‘takes’– GMT (286) higher than following primary GMT (286) higher than following primary

vaccinationvaccination– >95% with neutralizing antibody titers above >95% with neutralizing antibody titers above

putative protective level of 1:32putative protective level of 1:32– Non-inferior to DryvaxNon-inferior to Dryvax®®

– Cutaneous ResponseCutaneous Response– 84%, lower than Dryvax84%, lower than Dryvax®®, not non-inferior, not non-inferior– 94% in subjects without baseline antibody94% in subjects without baseline antibody

61

Mechanisms and Detection of MyocarditisMechanisms and Detection of Myocarditis and and

Outcomes and Incidence of Smallpox Outcomes and Incidence of Smallpox Vaccine-Related MyocarditisVaccine-Related Myocarditis

Jay W. Mason, MDJay W. Mason, MDProfessor of Medicine, Former Chief of Cardiology, Professor of Medicine, Former Chief of Cardiology,

University of UtahUniversity of Utah

Professor of Medicine, Former Chair of Medicine, Professor of Medicine, Former Chair of Medicine, University of KentuckyUniversity of Kentucky

62

TopicsTopics

• Mechanism of Viral MyocarditisMechanism of Viral Myocarditis

• Detection of MyocarditisDetection of Myocarditis

• Outcomes of MyocarditisOutcomes of Myocarditis– Classic myocarditis vs.Classic myocarditis vs.– Smallpox vaccine-related myocarditisSmallpox vaccine-related myocarditis

• Incidence of Smallpox Vaccine-related Incidence of Smallpox Vaccine-related MyocarditisMyocarditis

63

Mechanism of Viral MyocarditisMechanism of Viral Myocarditis

64

Triphasic Disease Process in Triphasic Disease Process in Classic MyocarditisClassic Myocarditis

65

Detection of MyocarditisDetection of Myocarditis

66

Current Methods for DiagnosisCurrent Methods for Diagnosis

• Endomyocardial biopsy Endomyocardial biopsy – Histology, inflammatory markers, viral nucleic acid Histology, inflammatory markers, viral nucleic acid

sequencessequences

• Imaging Imaging – MRI, ultrasound, nuclear scintigraphyMRI, ultrasound, nuclear scintigraphy

• Circulating Immune markersCirculating Immune markers

• ECGECG– Sensitivity: 47%, Morgera 1992Sensitivity: 47%, Morgera 1992

• Troponin Troponin – Sensitivity: 34% - 71%, Specificity: 86% - 94%Sensitivity: 34% - 71%, Specificity: 86% - 94%

• Clinical History Clinical History – Sensitivity: 53%, USMTTSensitivity: 53%, USMTT

67

* Subjects Hospitalized* Subjects Hospitalized

** Case not reviewed by CAP, but by Medical Monitor** Case not reviewed by CAP, but by Medical Monitor

ACAM2000 Clinical Trials ACAM2000 Clinical Trials Myocarditis Case SummaryMyocarditis Case SummarySubject Subject NumberNumber Clinical SymptomsClinical Symptoms ECGECG TroponinTroponin ECHO +ECHO +

20632063 No SymptomsNo Symptoms ++ –– ––

023190023190 No SymptomsNo Symptoms ++ –– ––

056111056111 No SymptomsNo Symptoms ++ ++ ++

094114094114 No SymptomsNo Symptoms ++ ++ ++

004103004103 Mild Ex intolMild Ex intol ++ –– ––

054106*054106* CP, DOE, Palps, CP, DOE, Palps, Ex tol Ex tol ++ ++ ––

048116*048116* CP, CP, Ex tol Ex tol ++ ++ ––

080112080112 DOE, PalpsDOE, Palps ++ –– ––

1238**1238** CPCP ++ ++ ––

065137065137 EquivocalEquivocal –– ++ ++

TotalTotal 6 / 106 / 10 9 / 109 / 10 6 / 106 / 10 3 / 103 / 10

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ACAM2000 Clinical Trials ACAM2000 Clinical Trials Myocarditis Case Summary Myocarditis Case Summary (Continued)

CAP ClassificationCAP Classification SubjectSubject TxTx Day of OnsetDay of Onset OutcomeOutcome

Suspected Subclinical Myocarditis

20632063

023190023190ACAM2000ACAM2000

ACAM2000ACAM20001414

99ResolvedResolved

ResolvedResolved

Probable Subclinical Myocarditis

056111056111

094194094194ACAM2000ACAM2000

ACAM2000ACAM20001010

99ResolvedResolved

ResolvedResolved

Suspect MyocarditisSuspect Myocarditis 004103004103 DryvaxDryvax®® 2020 ResolvedResolved

Probable MyocarditisProbable Myocarditis 048116048116

080112080112

054106054106

12381238

065137065137

ACAM2000ACAM2000

ACAM2000ACAM2000

DryvaxDryvax®®

ACAM2000ACAM2000

DryvaxDryvax®®

1111

99

1111

1010

99

ResolvedResolved

ResolvedResolved

ResolvedResolved

ResolvedResolved

OngoingOngoing

69

Outcomes of MyocarditisOutcomes of Myocarditis

70

Outcome in US Myocarditis Treatment TrialOutcome in US Myocarditis Treatment Trial

71

Incidence of Smallpox Incidence of Smallpox Vaccine-Related MyocarditisVaccine-Related Myocarditis

72

Incidence of “Myocarditis” Depends on Incidence of “Myocarditis” Depends on Primary Diagnostic Criteria – Recent Experience Primary Diagnostic Criteria – Recent Experience Consistent with the Past Consistent with the Past

SourceSource YearYear VaccineesVaccinees CasesCases IncidenceIncidence ResolutionResolution OnsetOnset DeathDeath

Self-ReportingSelf-Reporting

New YorkNew York 19471947 5M5M 11 0.00002%0.00002% N/AN/A NRNR 1*1*

FinlandFinland 1977 – 19791977 – 1979 60,00060,000 1010 0.02%0.02% UNKUNK NRNR 1**1**

DOD – DryvaxDOD – Dryvax®® 2002 – 20072002 – 2007 1.2M1.2M 140140 0.01%0.01% 8 / 53 Unresolved8 / 53 Unresolved <26d<26d 3***3***

CDC – DryvaxCDC – Dryvax®® 2002 – 20072002 – 2007 40,44940,449 2121 0.05%0.05% 3 Unresolved3 Unresolved <44d<44d 00

ECG and/or Serum MarkersECG and/or Serum Markers

Helle (Finland)Helle (Finland) 19741974 234234 88 3.4%3.4% 6 Resolved, 2 LTFU6 Resolved, 2 LTFU NRNR 00

Ahlborg (Swe)Ahlborg (Swe) 19631963 286 (re-vaccinees)286 (re-vaccinees) 33 1.0%1.0% Not followed upNot followed up NRNR 00

Acambis-DryvaxAcambis-Dryvax®® 2003 – 20042003 – 2004289 (P3) 289 (P3)

868 868 (all studies)(all studies)

33

33

1.04%1.04%

0.35%0.35%1 Case Unresolved1 Case Unresolved

<21d<21d00

ACAM2000ACAM2000 2003 – 20042003 – 2004873 (P3)873 (P3)

2983 2983 (all studies)(all studies)

55

77

0.57%0.57%

0.23%0.23%All ResolvedAll Resolved

<12d<12d

<14d<14d00

** At autopsyAt autopsy

**** Publication unclear whether death was in a smallpox vaccineePublication unclear whether death was in a smallpox vaccinee

****** 2 cases classified as possible Vaccinia-related myocarditis, although neither case has 2 cases classified as possible Vaccinia-related myocarditis, although neither case has confirmed cause of death as myocarditis; 1 case is still pendingconfirmed cause of death as myocarditis; 1 case is still pending

73


• Incidence of smallpox vaccine-related myocarditisIncidence of smallpox vaccine-related myocarditis– Highly dependent on case ascertainment Highly dependent on case ascertainment

and definitionand definition– < 1% with most rigorous case ascertainment < 1% with most rigorous case ascertainment

and definitionand definition– Not increased by ACAM2000Not increased by ACAM2000

• Spontaneous resolution in majoritySpontaneous resolution in majority

• Clinical history, troponin and ECGClinical history, troponin and ECG– Only practical large scale detection methodsOnly practical large scale detection methods– Sensitivity and specificity adequateSensitivity and specificity adequate

74

ACAM2000 Risk Management Plan ACAM2000 Risk Management Plan

(PVG Program & RiskMAP)(PVG Program & RiskMAP)

Michael Watson, MD, PhDMichael Watson, MD, PhDExecutive Vice President of Executive Vice President of Research and DevelopmentResearch and Development

75

ACAM2000 Clinical Trial ExperienceACAM2000 Clinical Trial Experience

• ACAM2000 well toleratedACAM2000 well tolerated– Similar or better safety profile to DryvaxSimilar or better safety profile to Dryvax®® for for

all AEsall AEs

• Relatively few SAEsRelatively few SAEs

• Most important findingMost important finding– ““Myocarditis” in ACAM2000 (0.57%) Myocarditis” in ACAM2000 (0.57%)

and Dryvaxand Dryvax®® (1.04%) (1.04%)– Case ascertainment & definition dependentCase ascertainment & definition dependent– ACAM2000 Phase III ACAM2000 Phase III prospectivelyprospectively

assessed ECG, enzymes & symptomsassessed ECG, enzymes & symptoms

76

ACAM2000 PVG Program GoalsACAM2000 PVG Program Goals

• Monitor for rarer SAEs – signal detectionMonitor for rarer SAEs – signal detection

• Establish more precise incidence rate Establish more precise incidence rate for possible “myocarditis”for possible “myocarditis”

• Assess short, medium & long-term Assess short, medium & long-term outcome for possible “myocarditis” casesoutcome for possible “myocarditis” cases

77

Elements of ACAM2000 PVG ProgramElements of ACAM2000 PVG Program

ACAM2000 ACAM2000 licensurelicensure Year 1Year 1 Year 2Year 2 Year 3Year 3

General Signal detection + case finding General Signal detection + case finding for “Myocarditis” Registryfor “Myocarditis” Registry

Routine PVG (spontaneous reporting*)Routine PVG (spontaneous reporting*)

Enhanced Surveillance (ESAV)Enhanced Surveillance (ESAV)

Prospective trial + case finding for Prospective trial + case finding for Myocarditis RegistryMyocarditis Registry

Phase IV TrialPhase IV Trial

Long-term Follow-upLong-term Follow-up

Myocarditis RegistryMyocarditis Registry

* Routine PVG and myocarditis registry continue through life of product* Routine PVG and myocarditis registry continue through life of product

78

ACAM2000 Routine PharmacovigilanceACAM2000 Routine Pharmacovigilance

• In collaboration with DoD and CDCIn collaboration with DoD and CDC

• Expedited reporting agreement with FDAExpedited reporting agreement with FDA

• Meet FDA Regulatory Reporting ReqMeet FDA Regulatory Reporting Req– VAERS for spontaneously reported eventsVAERS for spontaneously reported events– PSURs (quarterly x 3 years; annually thereafter)PSURs (quarterly x 3 years; annually thereafter)– Foreign reports, literatureForeign reports, literature

• Acambis PVG: Validated Safety Database (Argus) Acambis PVG: Validated Safety Database (Argus) operationaloperational

• Cardiac AEs entered into registryCardiac AEs entered into registry

• Under-reporting expected of any passive systemUnder-reporting expected of any passive system

79

ACAM2000 Enhanced Surveillance ProgramACAM2000 Enhanced Surveillance Program

• In collaboration with DoDIn collaboration with DoD

• Objective: collect larger cohort of possible Objective: collect larger cohort of possible “myocarditis” for follow-up“myocarditis” for follow-up

• Identify cases for Myocarditis RegistryIdentify cases for Myocarditis Registry

• Signal detection and SAEs and AEs Signal detection and SAEs and AEs of interestof interest

80

Enhanced Surveillance (>100,000)Enhanced Surveillance (>100,000)

Direct from subject, cards & emailDirect from subject, cards & email

Potential signals/AEs of interestPotential signals/AEs of interest

Cardiac events of interestCardiac events of interest

81

ACAM2000 Phase IV Trial (N=10,000+)ACAM2000 Phase IV Trial (N=10,000+)

GoalsGoals

• More precise estimate of incidence More precise estimate of incidence of possible “myocarditis” in vaccine of possible “myocarditis” in vaccine recipients, according to symptoms, recipients, according to symptoms, signs, labs and investigationssigns, labs and investigations

• Assess short, medium & long-term Assess short, medium & long-term outcome of eventsoutcome of events

• Identify other SAEs of interestIdentify other SAEs of interest

82

ACAM2000 Phase IV TrialACAM2000 Phase IV Trial

• In collaboration with DoD (deployable troops, In collaboration with DoD (deployable troops, informed consent)informed consent)

• Initiate within 12 months of product licensureInitiate within 12 months of product licensure

• Multicenter safety trial at 3-5 large military postsMulticenter safety trial at 3-5 large military posts

• Potentially 10,000+ (to be defined) participants vaccinated Potentially 10,000+ (to be defined) participants vaccinated with ACAM2000 alonewith ACAM2000 alone

– Investigating possible control groupInvestigating possible control group

• Anticipated time to complete: 2 years from first Anticipated time to complete: 2 years from first subject insubject in

• Ongoing organizational discussions to align with Ongoing organizational discussions to align with DoD prioritiesDoD priorities

83

Phase IV Schedule of EventsPhase IV Schedule of Events

Other identified eventsOther identified events

Follow-upFollow-up

IfIfpositive…positive…

Screening, informed consentScreening, informed consent

Medical visitMedical visit

Medical visitMedical visit

84

ACAM2000 Myocarditis RegistryACAM2000 Myocarditis Registry

• Maintained by DoD Vaccine Health Care Maintained by DoD Vaccine Health Care Centers (VHC)Centers (VHC)

• Objective: ascertain long-term outcome Objective: ascertain long-term outcome of acute possible “myocarditis” related of acute possible “myocarditis” related to smallpox vaccineto smallpox vaccine

– Follow-up period to a minimum of Follow-up period to a minimum of 2 years after onset (annual visits) 2 years after onset (annual visits) and longer for cases that remain and longer for cases that remain symptomaticsymptomatic

85

Other Action under ConsiderationOther Action under Consideration

• Retrospective cohort or case control studyRetrospective cohort or case control study

– Vaccination against smallpox was common prior Vaccination against smallpox was common prior to 1970to 1970

– No evidence for smallpox vaccine as cause No evidence for smallpox vaccine as cause of significant numbers of Dilated Cardiomyopathy of significant numbers of Dilated Cardiomyopathy (DCM)(DCM)

– Cohort or case control studies could assess the Cohort or case control studies could assess the strength of association of smallpox vaccine with strength of association of smallpox vaccine with DCM 20-40 years laterDCM 20-40 years later• CDCCDC• Framingham Framingham • Swedish or Finnish military cohortsSwedish or Finnish military cohorts

86

Risk Minimization Action PlanRisk Minimization Action Plan(RiskMAP)(RiskMAP)

87

Targets for Risk MinimizationTargets for Risk Minimization

• Potential vaccineesPotential vaccinees

• VaccineesVaccinees

• Contacts of vaccineesContacts of vaccinees

• Vaccinating physiciansVaccinating physicians

• Follow-up physiciansFollow-up physicians

88

Risks to be MinimizedRisks to be Minimized

• Auto-inoculation especially ocularAuto-inoculation especially ocular

• Secondary transmissionSecondary transmission

• Eczema in primary and secondary contactsEczema in primary and secondary contacts

• Immuno-compromisedImmuno-compromised

• PregnancyPregnancy

• Cardiac adverse eventsCardiac adverse events

• EncephalitisEncephalitis

• Allergy to vaccine and/or componentsAllergy to vaccine and/or components

89

Practical and Accessible ToolsPractical and Accessible Tools

90

• Extensive, repeated, clear advice have resulted in Extensive, repeated, clear advice have resulted in far fewer EV and secondary transmission cases than far fewer EV and secondary transmission cases than previously seenpreviously seen

Auto-innoculation and Secondary TransmissionAuto-innoculation and Secondary Transmission

91

Eczema in Vaccinee and ContactsEczema in Vaccinee and Contacts

• Screening Form 600 currently usedScreening Form 600 currently used

• Form records responses to:Form records responses to:– Does subject have atopic dermatitis or other Does subject have atopic dermatitis or other

chronic skin conditions chronic skin conditions – Did subject have atopic dermatitis as a child Did subject have atopic dermatitis as a child – Health status of people in the subject’s Health status of people in the subject’s

householdhousehold

• In light of recent case of EV, visibility and In light of recent case of EV, visibility and guidance will be further increasedguidance will be further increased

92

Immuno-compromisedImmuno-compromised

• Screening Form 600 currently usedScreening Form 600 currently used

• Form records information regarding:Form records information regarding:– Subject’s immune system (e.g., immuno-Subject’s immune system (e.g., immuno-

deficiency due to cancer treatment, deficiency due to cancer treatment, transplantation, AIDS, other conditions)transplantation, AIDS, other conditions)

– Subject’s HIV statusSubject’s HIV status

93

Inadvertent Use In PregnancyInadvertent Use In Pregnancy

• Screening FormScreening Form

• Pregnancy TestPregnancy Test

94

Minimization of Cardiac AEsMinimization of Cardiac AEs

• Clear screening for and exclusion of Cardiac risk factorsClear screening for and exclusion of Cardiac risk factors– History of anginaHistory of angina– An earlier heart attackAn earlier heart attack– Artery diseaseArtery disease– Congestive heart failureCongestive heart failure– CardiomyopathyCardiomyopathy– Stroke, “mini stroke,”Stroke, “mini stroke,”– Chest pain or shortness of breath with activityChest pain or shortness of breath with activity

• Or three or more of the following cardiac risk factors:Or three or more of the following cardiac risk factors:– Current smoker or tobacco userCurrent smoker or tobacco user– High blood pressureHigh blood pressure– High cholesterol or triglyceridesHigh cholesterol or triglycerides– High blood sugarHigh blood sugar– Heart condition before age 50 in a parent, brother, Heart condition before age 50 in a parent, brother,

or sisteror sister

95

Other Risk Minimization/Management Other Risk Minimization/Management Elements for Myo/PericarditisElements for Myo/Pericarditis

• Vaccination 30-60 days prior to deployment – cases Vaccination 30-60 days prior to deployment – cases appear mean of 11 days after vaccinationappear mean of 11 days after vaccination

• Algorithm for identifying and managing potential Algorithm for identifying and managing potential cases of myo/pericarditiscases of myo/pericarditis

• 6 month non-deployable period and specific 6 month non-deployable period and specific physical exercise form for all potential casesphysical exercise form for all potential cases

• Ongoing immuno-genetic studies to try and identify Ongoing immuno-genetic studies to try and identify at-risk groups at-risk groups

• 140 cases of myo/pericarditis among 1.2 million 140 cases of myo/pericarditis among 1.2 million vaccineesvaccinees

96

EncephalitisEncephalitis

• Very rareVery rare

• No clearly identified risk factorsNo clearly identified risk factors

• Unlikely to be pre-existing neurological Unlikely to be pre-existing neurological conditions in active military personnelconditions in active military personnel

97

ComplianceCompliance

• DoD Regional Analysts conduct hospital DoD Regional Analysts conduct hospital visits to check compliance with use of visits to check compliance with use of screening forms and educational materialsscreening forms and educational materials

98

Planned Additional Risk Minimization ToolsPlanned Additional Risk Minimization Tools

• Medication guide – first for a vaccineMedication guide – first for a vaccine

• Work closely with DoD and CDC to ensure Work closely with DoD and CDC to ensure consistency and sharing of information consistency and sharing of information and explore tools for assessing and explore tools for assessing compliance and impact of toolscompliance and impact of tools

99

Summary & RecommendationsSummary & Recommendations

• Extensive group of proven tools availableExtensive group of proven tools available

• Increase visibility of eczema warningsIncrease visibility of eczema warnings

• Ongoing work to try to identify risk factors Ongoing work to try to identify risk factors for myo/pericarditisfor myo/pericarditis

• Explore tools to assess vaccinee and Explore tools to assess vaccinee and physician compliancephysician compliance

• Ensure ongoing review and revision Ensure ongoing review and revision as requiredas required

Documents

1 Introduction to ACAM2000 Smallpox Vaccine David Wonnacott, PhD Senior Vice President of Quality and Regulatory