ST-246 antiviral efficacy in a nonhuman primate monkeypox model: determination of the minimal effective dose and human dose justification

Abstract

Therapeutics for the treatment of pathogenic orthopoxvirus infections are being sought. In the absence of patients with disease, animal models of orthopoxvirus disease are essential for evaluation of the efficacies of antiviral drugs and establishment of the appropriate dose and duration of human therapy. Infection of nonhuman primates (NHP) by the intravenous injection of monkeypox virus has been used to evaluate a promising therapeutic drug candidate, ST-246. ST-246 administered at 3 days postinfection (which corresponds to the secondary viremia stage of disease) at four different doses (from 100 mg/kg of body weight down to 3 mg/kg) once a day for 14 days was able to offer NHP 100% protection from a lethal infection with monkeypox virus and reduce the viral load and lesion formation. In NHP, the administration of ST-246 at a dose of 10 mg/kg/day for 14 days resulted in levels of blood exposure comparable to the levels attained in humans administered 400 mg in the fed state. These results suggest that administration of an oral dosage of 400 mg once daily for 14 days will be effective for the prevention or treatment of smallpox or monkeypox infections in humans.

Figures

FIG. 1.

Disease outcomes for NHP (three NHP per treatment group) infected with 5 × 107 PFU of MPX and treated with either vehicle alone or ST-246 administered at 3, 10, 30, or 100 mg/kg/day starting at day 3 postinfection. (a) Virus level in tissues 3 dpi and just prior to initiation of drug treatment. (b) Kaplan-Meier survival curve (log-rank test, all ST-246 groups, P < 0.001). (c) Maximum viral DNA by treatment and day postinfection. Bars, means; triangle, individual values (for 100-mg/kg ST-246-treated group, P < 0.001; for 30- and 10-mg/kg ST-246-treated groups, P < 0.01; for 10-mg/kg ST-246-treated group, P < 0.05). (d) Maximum lesion count by treatment group. Bars, means; triangles, individual values (for all ST-246-treated groups, P < 0.001).

FIG. 2.

Average lesion number and viral load of NHP (three NHP per treatment group) infected with 5 × 107 PFU of MPX and treated with either vehicle alone or ST-246 administered once per day for 14 days starting at day 3 postinfection. Viral lesion numbers (A, C, E, and G) and DNA levels (B, D, F, and H) were measured for animals treated with vehicle (squares) or ST-246 at 100 mg/kg (A and B; triangles), 30 mg/kg (C and D; inverted triangles), 10 mg/kg (E and F; diamonds), or 3 mg/kg (G and H; circles). Each symbol represents the data for an individual animal. The data from the vehicle-treated animals is included in each panel for comparison purposes. The geometric mean is shown as a solid line through the data points. The lower limit of quantification for DNA levels measured by quantitative PCR assay is shown as a black dashed line. All vehicle-treated animals either died or were euthanized (daggers) due to MPX infection between day 11 and 14 postinfection. A one-way ANOVA model generated a P value of <0.001 for all treatment groups compared to the results for the vehicle-treated control group.