Smallpox vaccine in combination with ST-246

Robert Jordan, Ph.D.SIGA Technologies, Inc

FDA – Public Hearing May 17, 2007

Smallpox Deployment Scenario

ACAM-2000

ST-246

MVA

Exposure

Incubation Rash……………DeathFever

~ 14 days ~ 3 days ~ 21 days

SentinelCase

Golden HoursST-246

ST-246 Progress to Date

ST-246 is a potent, non-toxic and specific inhibitor oforthopoxvirus replication

ST-246 is effective in multiple rodent challenge models againstorthopoxvirus induced pathogenesis and/or disease

ST-246 is effective against monkeypox and variola virus in a non-humanprimate model of orthopoxvirus disease

ST-246 is orally bioavailable with excellent PK parameters

ST-246 IND approved, Fast-Track status granted

Orphan Drug Designation for prevention and treatment of smallpox approved

Human clinical studies with ST-246 are underway

H

H

N

O

O

HNO

F F

F

H

H

ST-246

ST-246 Target is F13L

Systemic SpreadDisease

Cell-to-Cell SpreadLocal Infection

Replication&

AssemblyImmature

Virus(IV)

IntracellularMature Virus

(IMV)

ExtracellularEnveloped Virus

(EEV)

F13L

No Disease*ST-246

TGN PM

*Animals infected in presence of ST-246 develop a protective immune response

Days Post-Challenge

0 5 10 15 20 25 30

% S

urv

ival

-20

0

20

40

60

80

100

120

Vehicle sid Cidofovir ST-246 1 mg/kg sid ST-246 5 mg/kg sid ST-246 20 mg/kg sid ST-246 100 mg/kg sid ST-246 0.5 mg/kg bid ST-246 2.5 mg/kg bid ST-246 10 mg/kg bid ST-246 50 mg/kg bid Vehicle bid

A

Days Post-Challenge

0 5 10 15 20 25 30

% o

f S

tart

ing

Wei

gh

t

60

80

100

120

140

160

Vehicle sid Cidofovir ST-246 1 mg/kg sid ST-246 5 mg/kg sid ST-246 20 mg/kg sid ST-246 100 mg/kg sid ST-246 0.5 mg/kg bid ST-246 2.5 mg/kg bid ST-246 10 mg/kg bid ST-246 50 mg/kg bid Vehicle bid

B

I.N. vaccinia virus challenge in miceDose optimization

No drug ST-246

ST-246 protects animals from all orthopoxvirus pathogens tested (VV, CPX, ECTV, RPV, MPX, VaV)

Addition of ST-246 up to 72h post infection protects animals from disease & death

ST-246 reduces viral replication in lung by 6 logs

ST-246 treatment in combination with Dryvax elicits a protective immune response.

Animal Efficacy Highlights

Prophylaxis - Prevent disease in non-vaccinated individuals

Post-exposure Prophylaxis - Treat non-symptomatic individuals previously exposed to smallpox

Therapeutic – Treat individuals exhibiting smallpox disease symptoms

Adjunct to Vaccination Use in combination with vaccines to prevent smallpox disease Prevent vaccine-related complications Prevent disease in those populations unable to be vaccinated

Uses for the ST-246 Smallpox Antiviral

Dryvax Dermal Challenge/Vehicle Treatment

Dryvax Dermal Challenge/SIGA-246 Treatment

Cytokine Release Assay

IFN-g Release (48 hrs)

0 250 500 750 1000 1250 1500 1750

Naïve

Vaccine

Vaccine/ST-246

Concentration (pg/ml/million cells)

Mock-A20

VV-A20

IFN-g Release (48 hrs)

0 100 200 300 400 500 600 700 800

Naïve

Vaccine

Vaccine/ST-246

Concentration (pg/ml/million cells)

Mock-A20

VV-A20

Acute Response

Memory Response

Anti-Vaccinia IgG

Anti-VV IgG

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

5 25 125 625 3125 15625 78125 390625

Recprocal Serum DIlution

OD

49

0

Naive

Vaccine

Vaccine/ST-246

Anti-VV IgG

0.00

0.50

1.00

1.50

2.00

2.50

5 25 125 625 3125 15625 78125 390625

Recprocal Serum DIlution

OD

49

0

Naive

Vaccine

Vaccine/ST-246

Acute Response

Memory Response

ST-246/Dryvax Conclusions

Vaccine/ST-246 combination elicits enhanced IFN-gamma responses (primarily attributable to CD8 T cells) at both acute and memory phases of the immune response

Vaccine/ST-246 combination elicits equivalent proliferative and humoral responses

Vaccine/ST-246 combination elicits equivalent protective immunity

ST-246 in combination with a smallpox vaccine could protect individuals from severe disease prior to development of protective immunity