BACKGROUND: Smallpox was declared eradicated in 1980, but variola virus (VARV), 
which causes smallpox, still exists. There is no known effective treatment for 
smallpox; therefore, tecovirimat is being developed as an oral smallpox therapy. 
Because clinical trials in a context of natural disease are not possible, an 
alternative developmental path to evaluate efficacy and safety was needed.
METHODS: We investigated the efficacy of tecovirimat in nonhuman primate 
(monkeypox) and rabbit (rabbitpox) models in accordance with the Food and Drug 
Administration (FDA) Animal Efficacy Rule, which was interpreted for smallpox 
therapeutics by an expert advisory committee. We also conducted a 
placebo-controlled pharmacokinetic and safety trial involving 449 adult 
volunteers.
RESULTS: The minimum dose of tecovirimat required in order to achieve more than 
90% survival in the monkeypox model was 10 mg per kilogram of body weight for 14 
days, and a dose of 40 mg per kilogram for 14 days was similarly efficacious in 
the rabbitpox model. Although the effective dose per kilogram was higher in 
rabbits, exposure was lower, with a mean steady-state maximum, minimum, and 
average (mean) concentration (Cmax, Cmin, and Cavg, respectively) of 374, 25, 
and 138 ng per milliliter, respectively, in rabbits and 1444, 169, and 598 ng 
per milliliter in nonhuman primates, as well as an area under the 
concentration-time curve over 24 hours (AUC0-24hr) of 3318 ng×hours per 
milliliter in rabbits and 14,352 ng×hours per milliliter in nonhuman primates. 
These findings suggested that the nonhuman primate was the more conservative 
model for the estimation of the required drug exposure in humans. A dose of 600 
mg twice daily for 14 days was selected for testing in humans and provided 
exposures in excess of those in nonhuman primates (mean steady-state Cmax, Cmin, 
and Cavg of 2209, 690, and 1270 ng per milliliter and AUC0-24hr of 30,632 
ng×hours per milliliter). No pattern of troubling adverse events was observed.
CONCLUSIONS: On the basis of its efficacy in two animal models and 
pharmacokinetic and safety data in humans, tecovirimat is being advanced as a 
therapy for smallpox in accordance with the FDA Animal Rule. (Funded by the 
National Institutes of Health and the Biomedical Advanced Research and 
Development Authority; ClinicalTrials.gov number, NCT02474589 .).