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