Development of ST-246® for Treatment of Poxvirus Infections

Abstract

ST-246 (Tecovirimat) is a small synthetic antiviral compound being developed to treat pathogenic orthopoxvirus infections of humans. The compound was discovered as part of a high throughput screen designed to identify inhibitors of vaccinia virus-induced cytopathic effects. The antiviral activity is specific for orthopoxviruses and the compound does not inhibit the replication of other RNA- and DNA-containing viruses or inhibit cell proliferation at concentrations of compound that are antiviral. ST-246 targets vaccinia virus p37, a viral protein required for envelopment and secretion of extracellular forms of virus. The compound is orally bioavailable and protects multiple animal species from lethal orthopoxvirus challenge. Preclinical safety pharmacology studies in mice and non-human primates indicate that ST-246 is readily absorbed by the oral route and well tolerated with the no observable adverse effect level (NOAEL) in mice measured at 2000 mg/kg and the no observable effect level (NOEL) in non-human primates measured at 300 mg/kg. Drug substance and drug product processes have been developed and commercial scale batches have been produced using Good Manufacturing Processes (GMP). Human phase I clinical trials have shown that ST-246 is safe and well tolerated in healthy human volunteers. Based on the results of the clinical evaluation, once a day dosing should provide plasma drug exposure in the range predicted to be antiviral based on data from efficacy studies in animal models of orthopoxvirus disease. These data support the use of ST-246 as a therapeutic to treat pathogenic orthopoxvirus infections of humans.

Orthopoxvirus targets for the development of new antiviral agents

“…The mechanism of action of ST-246 appears to be similar to IMCBH in that drug resistant mutations mapped to F13L, however ST-246 was very active in animal models of vaccinia, cowpox, ectromelia, monkeypox, and variola virus infections (Jordan et al, 2010). This mechanism of action confirmed that the formation of EEV was important in the pathogenesis of orthopoxviruses and is consistent with genetic data that indicated that the inhibition of EEV production was sufficient to limit the spread of infection in vivo and prevent mortality (Jordan et al, 2010; Payne and Kristensson, 1985). …”

Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy

“…Both these drugs had similar mechanisms of antiviral action, which were associated with blocking the process of formation of the virion envelope in infected cells negatively influencing the formation of a pathogenetically significant extracellular enveloped virus (Jordan et al, 2010;Shishkina et al, 2015). ICR mice were given orally 0.2 ml of suspension of these compounds at the dose of 60 mg (g body weight)…”

Orthopoxvirus Inhibitors that are Active in Animal Models: An Update from 2008 to 2012

“…CMX001 converts to cidofovir in vivo , and thus has the same mode of action. ST-246 is a unique compound that blocks a late step in virus assembly by preventing intracellular envelope virus formation and subsequent virus egress from the cell [19,20]. This greatly restricts the spread of virus in vivo .…”