title: Efficacy of delayed brincidofovir treatment against a lethal rabbitpox virus challenge in New Zealand White rabbits.
abstract: In the event of a bioterror attack with variola virus (smallpox), exposure may only be identified following onset of fever. To determine if antiviral therapy with brincidofovir (BCV; CMX001) initiated at, or following, onset of fever could prevent severe illness and death, a lethal rabbitpox model was used. BCV is in advanced development as an antiviral for the treatment of smallpox under the US Food and Drug Administration's 'Animal Rule'. This pivotal study assessed the efficacy of immediate versus delayed treatment with BCV following onset of symptomatic disease in New Zealand White rabbits intradermally inoculated with a lethal rabbitpox virus (RPXV), strain Utrecht. Infected rabbits with confirmed fever were randomized to blinded treatment with placebo, BCV, or BCV delayed by 24, 48, or 72 h. The primary objective evaluated the survival benefit with BCV treatment. The assessment of reduction in the severity and progression of clinical events associated with RPXV were secondary objectives. Clinically and statistically significant reductions in mortality were observed when BCV was initiated up to 48 h following the onset of fever; survival rates were 100%, 93%, and 93% in the immediate treatment, 24-h, and 48-h delayed treatment groups, respectively, versus 48% in the placebo group (p < 0.05 for each vs. placebo). Significant improvements in clinical and virologic parameters were also observed. These findings provide a scientific rationale for therapeutic intervention with BCV in the event of a smallpox outbreak when vaccination is contraindicated or when diagnosis follows the appearance of clinical signs and symptoms.
authors.affiliation: Chimerix, Durham, NC, USA. Electronic address: ggrossi@chimerix.com.
authors.forename: Irma M
authors.initials: IM
authors.lastname: Grossi
authors.affiliation: Chimerix, Durham, NC, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Foster
authors.affiliation: Battelle, West Jefferson, OH, USA.
authors.forename: Melicia R
authors.initials: MR
authors.lastname: Gainey
authors.affiliation: Battelle, West Jefferson, OH, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Krile
authors.affiliation: Chimerix, Durham, NC, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Dunn
authors.affiliation: Chimerix, Durham, NC, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brundage
authors.affiliation: Chimerix, Durham, NC, USA.
authors.forename: Jody M
authors.initials: JM
authors.lastname: Khouri
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents / Q000627:therapeutic use; D001831:Body Temperature; D001835:Body Weight; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004311:Double-Blind Method; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D011213:Poxviridae Infections / Q000188:drug therapy; D011817:Rabbits; D012899:Smallpox / Q000188:drug therapy*; D015996:Survival Rate; D016896:Treatment Outcome; D014611:Vaccination; D014615:Vaccinia / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology / Q000821:virology; D014616:Vaccinia virus / Q000187:drug effects*; D012901:Variola virus; D019562:Viral Load / Q000187:drug effects
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; D063065:Organophosphonates; C525733:brincidofovir; D003596:Cytosine
keywords: Antiviral; Brincidofovir; CMX001; Orthopoxvirus; Smallpox