Oral Tecovirimat for the Treatment of Smallpox

Abstract

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 .).

Figures

Figure 1. Efficacy and Pharmacokinetic Profiles of Tecovirimat in Animal Models

On day 0, nonhuman primates (Panels A and B) and rabbits (Panels C and D) were infected with a lethal dose of monkeypox virus or rabbitpox virus, respectively. Survival was monitored for 18 to 42 days after infection, indicated on the horizontal axis labels. Tecovirimat was administered by oral gavage at doses ranging from 0.3 to 20 mg per kilogram of body weight in nonhuman primates and from 20 to 120 mg per kilogram in rabbits. Tecovirimat was administered for 14 consecutive daily doses starting on day 4 after infection, after the onset of clinical signs (pock lesions in nonhuman primates and fever and viremia in rabbits) in each study. Comparison of the exposures required for efficacy in rabbits and nonhuman primates showed that the nonhuman primate was the more conservative model, with higher exposures required for full effectiveness. Therefore, the exposure profiles of tecovirimat in plasma in nonhuman primates and humans were compared after the first dose (Panel E) and after the last dose at steady state (Panel F) to evaluate whether exposures in humans exceeded those in nonhuman primates, providing a reasonable expectation of efficacy in humans.

Figure 2. Differences in Survival Rates with Tecovirimat as Compared with Placebo

Shown is a forest-plot summary comparing differences in survival rates between tecovirimat and placebo in each study. The exact 95% confidence intervals (horizontal bars in the forest plot) are based on the score statistic of the difference in survival rates. The P value is from a one-sided Fisher’s exact test for the comparison of tecovirimat with placebo. Data from the study of dose exploration and pharmacokinetics in rabbits are not shown on the forest plot, since the study did not include a placebo control.