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.
Subject(s)
Cytosine/analogs & derivatives , Organophosphonates/therapeutic use , Smallpox/drug therapy , Vaccinia virus/drug effects , Vaccinia/drug therapy , Animals , Antibodies, Neutralizing , Antibodies, Viral , Antiviral Agents/therapeutic use , Body Temperature , Body Weight , Cytosine/administration & dosage , Cytosine/therapeutic use , Disease Models, Animal , Double-Blind Method , Organophosphonates/administration & dosage , Poxviridae Infections/drug therapy , Rabbits , Survival Rate , Treatment Outcome , Vaccination , Vaccinia/mortality , Vaccinia/physiopathology , Vaccinia/virology , Variola virus , Viral Load/drug effectsABSTRACT
Brincidofovir (BCV) has broad-spectrum in vitro activity against dsDNA viruses, including smallpox, and is being developed as a treatment for smallpox as well as infections caused by other dsDNA viruses. BCV has previously been shown to be active in multiple animal models of smallpox. Here we present the results of a randomized, blinded, placebo-controlled study of the efficacy and pharmacokinetics of a novel, "humanized" regimen of BCV for treatment of New Zealand White rabbits infected with a highly lethal inoculum of rabbitpox virus, a well characterized model of smallpox. Compared with placebo, a dose-dependent increase in survival was observed in all BCV-treatment groups. Concentrations of cidofovir diphosphate (CDV-PP), the active antiviral, in rabbit peripheral blood mononuclear cells (PBMCs) were determined for comparison to those produced in humans at the dose proposed for treatment of smallpox. CDV-PP exposure in PBMCs from rabbits given BCV scaled to human exposures at the dose proposed for treatment of smallpox, which is also currently under evaluation for other indications. The results of this study demonstrate the activity of BCV in the rabbitpox model of smallpox and the feasibility of scaling doses efficacious in the model to a proposed human dose and regimen for treatment of smallpox.
