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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. Sentinel Case. Exposure. Rash……………Death. Fever. Incubation. ~ 14 days. ~ 21 days. ~ 3 days. ACAM-2000. MVA. ST-246. Golden Hours. ST-246.

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Smallpox vaccine in combination with ST-246

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  1. Smallpox vaccine in combination with ST-246 Robert Jordan, Ph.D. SIGA Technologies, Inc FDA – Public Hearing May 17, 2007

  2. Sentinel Case Exposure Rash……………Death Fever Incubation ~ 14 days ~ 21 days ~ 3 days ACAM-2000 MVA ST-246 Golden Hours ST-246 Smallpox Deployment Scenario

  3. 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

  4. Cell-to-Cell Spread Local Infection Systemic Spread Disease ST-246Target is F13L No Disease* Replication & Assembly ST-246 F13L Immature Virus (IV) Intracellular Mature Virus (IMV) Extracellular Enveloped Virus (EEV) TGN PM *Animals infected in presence of ST-246 develop a protective immune response

  5. I.N. vaccinia virus challenge in mice Dose optimization No drug ST-246

  6. Animal Efficacy Highlights • 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.

  7. Uses for the ST-246 Smallpox Antiviral • 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

  8. Dryvax Dermal Challenge/Vehicle Treatment

  9. Dryvax Dermal Challenge/SIGA-246 Treatment

  10. Cytokine Release Assay Acute Response Memory Response

  11. Anti-Vaccinia IgG Acute Response Memory Response

  12. 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

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