The Role of Brincidofovir in Preparation for a Potential Smallpox Outbreak

Abstract

Smallpox (variola) virus is considered a Category A bioterrorism agent due to its ability to spread rapidly and the high morbidity and mortality rates associated with infection. Current recommendations recognize the importance of oral antivirals and call for having at least two smallpox antivirals with different mechanisms of action available in the event of a smallpox outbreak. Multiple antivirals are recommended due in large part to the propensity of viruses to become resistant to antiviral therapy, especially monotherapy. Advances in synthetic biology heighten concerns that a bioterror attack with variola would utilize engineered resistance to antivirals and potentially vaccines. Brincidofovir, an oral antiviral in late stage development, has proven effective against orthopoxviruses in vitro and in vivo, has a different mechanism of action from tecovirimat (the only oral smallpox antiviral currently in the US Strategic National Stockpile), and has a resistance profile that reduces concerns in the scenario of a bioterror attack using genetically engineered smallpox. Given the devastating potential of smallpox as a bioweapon, preparation of a multi-pronged defense that accounts for the most obvious bioengineering possibilities is strategically imperative.

Keywords: CMX001; antiviral; bioterrorism; bioweapon; brincidofovir; smallpox; variola virus.

Figure 1

Forest plot of BCV efficacy data in the rabbitpox model. The vertical dotted line is a reference for no risk difference (i.e., no drug effect). All studies included equal numbers of male and female rabbits. Studies CMX001-UFL-010, -011, and -012 were conducted at the University of Florida [14]. In these studies, BCV was administered orally at 20 mg/kg beginning at the first observation of lesions. In Study UFL-010, animals received a total of three doses of 20 mg/kg, one dose every 48 h (20/20/20 mg/kg q48h), while in Studies UFL-011 and -012, the animals received 1 or 2 doses, respectively. Studies CMX001-VIR-039 and -041 were conducted at Battelle [15,16]. In Study VIR-039, BCV was administered at the first observation of lesions. Animals received 5/5/5, 20/5/5, or 20/20/20 mg/kg q48h. In the pivotal study VIR-041, BCV was administered at the first observation of fever, or was delayed by 24, 48, or 72 h after fever. Animals received 20/5/5 mg/kg q48h. Treatment effect was estimated by calculating the risk difference for each study. A pooled estimate of the risk difference across all studies was estimated using meta-analysis methodology. For calculation of the risk difference in each study (right column (95% CI)), the treatment groups were combined into one group of BCV-treated animals, regardless of the level of efficacy in each dose group. The pooled estimate of the risk difference is 52% (95% CI: 65% to 38%), meaning the average mortality in BCV-treated animals is 52% lower on an absolute basis. Removing BCV doses above those used in Study CMX001-VIR-041 (20/5/5 mg/kg q48 h) from the analysis (i.e., 20/20/20 mg/kg q48h and 20/20 mg/kg q48h) shifts the pooled estimate of the risk difference to 41% (95% CI: 55% to 27%).

Figure 2

Survival by day of treatment initiation in the intranasal inoculation mousepox model. Data were pooled across studies and include different mouse strains, viral inoculum levels, and BCV dosage regimens. Data included for Studies CMX001-SLU-005, -006, -007, -008, -009, -011, -012, -013, -014, and CMX001-VIR-102 (initial BCV doses of 10 mg/kg to 30 mg/kg or placebo, single ± maintenance doses, treatment initiation Day 0 to Day 7, A Strain (A/NCR, A/J), SKH-1, C57Bl/6, and BALB/c mice). Individual studies included either male or female mice. All SKH-1, C57Bl/6, and BALB/c mice represented in the figure were female (N = 132, 110, and 55, respectively). A Strain mice included both males and females (N = 266 and 179, respectively). The numbers above the bars indicate the percentage survival. The number of animals for each treatment initiation day: Day 0 = 35, Day 1 = 20, Day 2 = 30, Day 3 = 75, Day 4 = 115, Day 5 = 144, Day 6 = 168, Day 7 = 44, PBO = 111. * Two-sided Fisher’s exact test, p < 0.0001 vs. placebo. No adjustments were made for multiple comparisons. These results have been previously published [17,18,19], with the exception of the BALB/c results (Study CMX001-VIR-102).