Small Molecule Inhibitors of Smallpox Virus Replication

DESCRIPTION (provided by applicant): Concern over the use of variola virus as a biological weapon has prompted interest in development of small molecule therapeutics for smallpox. Variola virus is highly transmissible and causes severe disease with high mortality rates. Currently, there is no FDA-approved drug for prevention or treatment of smallpox. The overall goal of this smallpox antiviral program is to advance through FDA approval a small molecule antiviral drug for treatment of smallpox. The final drug product will be a safe, effective, and orally administered antiviral compound taken three times or less daily to accommodate treatment, post-exposure prophylactic and prophylactic applications. Our current lead drug candidate, ST-246, is a novel orally bioavailable antiviral compound that is a potent and specific inhibitor of orthopoxvirus replication in vitro and in vivo. ST-246 was discovered during chemical optimization of an initial "hit" that came from a high throughput screen designed to identify inhibitors of vaccinia virus replication. ST-246 and related analogs inhibit vaccinia, cowpox, ectromelia (mousepox), monkeypox, camelpox and variola replication in cell culture but not other unrelated viruses. The compound is well tolerated and orally bioavailable in rodents and monkeys. Moreover, ST-246 protects mice from lethal challenge with vaccinia virus and ectromelia virus and inhibits orthopoxvirus induced disease in normal and immunodeficient mice. It is proposed in this application to advance ST-246 into clinical development by 1) optimizing dosing parameters for in vivo efficacy evaluations, 2) conducting scale up synthesis of ST-246 and initiating formulation studies for drug product manufacture in anticipation of initiating human safety and pharmacology clinical studies 3) completing IND-enabling toxicology assessments, and 4) conducting GLP animal efficacy experiments sufficient to meet animal efficacy rule requirements. These studies will support the investigational new drug (IND) application that will be submitted to the FDA to initiate human clinical trials.