title: 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.
authors.affiliation: SIGA Technologies, Inc., 4575 SW Research Way, Suite 230, Corvallis, OR 97333, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.forename: Arthur
authors.initials: A
authors.lastname: Goff
authors.forename: Annie
authors.initials: A
authors.lastname: Frimm
authors.forename: Michael L
authors.initials: ML
authors.lastname: Corrado
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hensley
authors.forename: Chelsea M
authors.initials: CM
authors.lastname: Byrd
authors.forename: Eric
authors.initials: E
authors.lastname: Mucker
authors.forename: Josh
authors.initials: J
authors.lastname: Shamblin
authors.forename: Tove' C
authors.initials: TC
authors.lastname: Bolken
authors.forename: Carly
authors.initials: C
authors.lastname: Wlazlowski
authors.forename: Wendy
authors.initials: W
authors.lastname: Johnson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Chapman
authors.forename: Nancy
authors.initials: N
authors.lastname: Twenhafel
authors.forename: Shanthakumar
authors.initials: S
authors.lastname: Tyavanagimatt
authors.forename: Adams
authors.initials: A
authors.lastname: Amantana
authors.forename: Jarasvech
authors.initials: J
authors.lastname: Chinsangaram
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hruby
authors.forename: John
authors.initials: J
authors.lastname: Huggins
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D054833:Isoindoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008252:Macaca fascicularis; D045908:Mpox, Monkeypox / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D008993:Monkeypox virus / Q000187:drug effects*; D016896:Treatment Outcome; D010797:Phthalimides
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; C505045:tecovirimat; D010797:Phthalimides