Efficacy of tecovirimat (ST-246) in nonhuman primates infected with variola virus (Smallpox)

Abstract

Naturally occurring smallpox has been eradicated but remains a considerable threat as a biowarfare/bioterrorist weapon (F. Fleck, Bull. World Health Organ. 81:917-918, 2003). While effective, the smallpox vaccine is currently not recommended for routine use in the general public due to safety concerns (http://www.bt.cdc.gov/agent/smallpox/vaccination). Safe and effective countermeasures, particularly those effective after exposure to smallpox, are needed. Currently, SIGA Technologies is developing the small-molecule oral drug, tecovirimat (previously known as ST-246), as a postexposure therapeutic treatment of orthopoxvirus disease, including smallpox. Tecovirimat has been shown to be efficacious in preventing lethal orthopoxviral disease in numerous animal models (G. Yang, D. C. Pevear, M. H. Davies, M. S. Collett, T. Bailey, et al., J. Virol. 79:13139-13149, 2005; D. C. Quenelle, R. M. Buller, S. Parker, K. A. Keith, D. E. Hruby, et al., Antimicrob. Agents Chemother., 51:689-695, 2007; E. Sbrana, R. Jordan, D. E. Hruby, R. I. Mateo, S. Y. Xiao, et al., Am. J. Trop. Med. Hyg. 76:768-773, 2007). Furthermore, in clinical trials thus far, the drug appears to be safe, with a good pharmacokinetic profile. In this study, the efficacy of tecovirimat was evaluated in both a prelesional and postlesional setting in nonhuman primates challenged intravenously with 1 × 10(8) PFU of Variola virus (VARV; the causative agent of smallpox), a model for smallpox disease in humans. Following challenge, 50% of placebo-treated controls succumbed to infection, while all tecovirimat-treated animals survived regardless of whether treatment was started at 2 or 4 days postinfection. In addition, tecovirimat treatment resulted in dramatic reductions in dermal lesion counts, oropharyngeal virus shedding, and viral DNA circulating in the blood. Although clinical disease was evident in tecovirimat-treated animals, it was generally very mild and appeared to resolve earlier than in placebo-treated controls that survived infection. Tecovirimat appears to be an effective smallpox therapeutic in nonhuman primates, suggesting that it is reasonably likely to provide therapeutic benefit in smallpox-infected humans.

Fig 1

Survival following VARV challenge by treatment group. Cynomolgus macaques were challenged with 1 × 10⁸ PFU VARV by the intravenous route on day 0 and were monitored for survival and signs of disease for 28 days postchallenge. All nonsurviving animals in the placebo group were preemptively humanely euthanized when moribund on days 13 and 14.

Fig 2

Total body lesion counts following VARV challenge by treatment group. Cynomolgus macaques were challenged with 1 × 10⁸ PFU VARV by the intravenous route on day 0. Lesions were counted daily over the entire body surface area and totaled for 28 days postchallenge. Treatment group averages are shown. For the placebo-treated group, values from days 13 to 22 are imputed (last observation carried forward) for animals that succumbed to disease on days 13 and 14 (indicated by asterisks) prior to study termination. Error bars indicate standard deviations.

Fig 3

Viremia (qPCR of viral DNA in blood) following VARV challenge by treatment group. Cynomolgus macaques were challenged with 1 × 10⁸ PFU VARV by the intravenous route on day 0. Every third day (and at unscheduled moribund euthanasia; see data point at day 14), DNA from blood samples was evaluated by qPCR for the presence and quantitation of viral genomes. Treatment group averages are shown. Error bars indicate standard deviations. In some instances, negative error is not displayed when the error extends to negative values (less than 0), due to plotting y axis data on a logarithmic scale. Unscheduled deaths (euthanasia due to moribund condition) in the placebo group are indicated by asterisks. Plotted data for the placebo group after day 14 are representative of the three surviving animals in the group. LLOQ, lower limit of quantitation (10,000 GC/ml of blood).

Fig 4

Throat swab plaque assay by treatment group. Cynomolgus macaques were challenged with 1 × 10⁸ PFU VARV by the intravenous route on day 0. Oropharyngeal swabs were taken on days 0, 2, 4, 7, 10, 13, 16, 19, and 22 and evaluated by plaque assay for live virus. Treatment group median values are shown. Wide variability within groups was observed, and error bars are omitted to prevent obscuring the data. Unscheduled deaths (euthanasia due to moribund condition) in the placebo group are indicated by asterisks. No samples were positive after day 13, and day 22 is the last day for which samples were evaluated.