# Presentation: 616096

## Smallpox vaccine in combination with ST-246					

**Smallpox vaccine in combination with ST-246****	****	****	****	****	**

**Robert Jordan, Ph.D.**
***SIGA Technologies, Inc***

**FDA – Public Hearing****	****	****May 17, 2007**

## Smallpox Deployment Scenario

## ST-246 Progress to Date

**  ****ST-246 is a potent, non-toxic and specific inhibitor of**
**	****orthopoxvirus replication**
**  ****ST-246 is effective in multiple rodent challenge models against**
**	****orthopoxvirus induced pathogenesis and/or disease**
** ****ST-246 is effective against monkeypox and variola virus in a non-human**
**	****primate 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  **

_**ST-246**_

## ST-246 Target is F13L

**Replication**
**&**
**Assembly**

**Immature**
**Virus**
**(IV)**

**Intracellular**
**Mature Virus**
**(IMV)**

**Extracellular**
**Enveloped Virus**
**(EEV)**

**F13L**

**No Disease***

**ST-246**

**TGN**

**PM**

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

## I.N. vaccinia virus challenge in mice

**I.N. vaccinia virus challenge in mice**
**Dose 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.

- 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

- 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

**Dryvax Dermal Challenge/SIGA-246 Treatment**

## Cytokine Release Assay 

**Acute Response**

**Memory Response**

## Anti-Vaccinia IgG 

**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