Efficacy of delayed brincidofovir treatment against a lethal rabbitpox virus challenge in New Zealand White rabbits

Grossi, Irma M.; Foster, Scott A.; Gainey, Melicia; Krile, Robert; Dunn, John A.; Brundage, Thomas M.; Khouri, Jody

doi:10.1016/j.antiviral.2017.04.002

Cited by 33 publications

(32 citation statements)

References 14 publications

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“…was most protective, however post-lesional treatment could provide significant protection up to 4 days p.i. (66-73%) (85,(90)(91)(92). A single BCV dose protected 7 of 12 animals (85).…”

Section: Brincidofovir Efficacy In Lethal Orthopoxvirus Systemic Chalmentioning

confidence: 99%

Efficacy of three key antiviral drugs used to treat orthopoxvirus infections: a systematic review

Yu¹,

Raj²

2019

Global Biosecurity

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Background: In a global political climate increasingly concerned about terrorism, bioterrorism agents such as smallpox would undoubtedly be catastrophic. Since WHO announced the eradication of smallpox in 1980, consequently discontinuing the worldwide vaccination campaign, today's population is either immunologically naïve or has waning levels of protection. Further, up to 25% of today's population are contraindicated for smallpox vaccination due to various immunodeficiency conditions. The aim of this study was to evaluate the efficacy of the anti-DNA antivirals cidofovir (CDV), brincidofovir (BCV) and tecovirimat against smallpox and other orthopoxviruses. As of July 2018, FDA approved tecovirimat as the first treatment for smallpox. Methods: A systematic review was conducted to identify relevant literature describing the efficacy and safety of CDV, BCV and tecovirimat including in vitro and in vivo animal studies, human safety trials and human case reports of orthopoxvirus infection. Results: 158 studies met the inclusion criteria. In vitro and in vivo animal studies have found that CDV, BCV and tecovirimat are highly efficacious when used therapeutically and prophylactically. They are partially protective in moderate, but not severe, immunodeficiency models. Clinical trials consistently report BCV and tecovirimat to be safe and well tolerated in humans. In human case reports, CDV, BCV and tecovirimat contributed to recovery from orthopoxvirus infection. BCV and tecovirimat demonstrate strong synergistic effect and may reduce risk of antiviralresistant strains. Conclusion: BCV and tecovirimat are particularly promising as anti-smallpox agents. Gaps in the literature indicate that further research should focus on developing more robust immunodeficiency and antiviral-resistance models.

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“…was most protective, however post-lesional treatment could provide significant protection up to 4 days p.i. (66-73%) (85,(90)(91)(92). A single BCV dose protected 7 of 12 animals (85).…”

Section: Brincidofovir Efficacy In Lethal Orthopoxvirus Systemic Chalmentioning

confidence: 99%

Efficacy of three key antiviral drugs used to treat orthopoxvirus infections: a systematic review

Yu¹,

Raj²

2019

Global Biosecurity

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“…One of the first effective drugs in clinical use as a parenteral treatment in severe OPV infections was cidofovir, a bisphosphonate developed at REGA, in Belgium [31,35]) and FDA approved against human cytomegalovirus (HCMV). The ether lipid analogue brincidofovir (CMX001), a prodrug of cidofovir, has shown efficacy in small animal models and is awaiting FDA approval [26,44,56,115,116,118,139]. The F13L virus egress inhibitor tecovirimat (ST-246, TPOXX®) has been independently developed to treat smallpox infections and has been FDA approved since 2018.…”

Section: Poxviridaementioning

confidence: 99%

Antivirals in medical biodefense

et al. 2020

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The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha-and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…BCV efficacy was subsequently demonstrated in randomized, blinded, placebo-controlled studies in the rabbitpox model, first at the University of Florida [ 14 ] and then at a contract research laboratory (Battelle Biomedical Research Center, West Jefferson, OH, USA) [ 15 ]. A pivotal study has been completed in compliance with Good Laboratory Practice (GLP) regulations [ 16 ]. In each study, a statistically significant survival benefit was demonstrated when treatment was initiated at the onset of clinical signs of disease in the rabbits, i.e., after detection of lesions or, in the GLP study at up to 48 h after the onset of fever [ 15 , 16 ].…”

Section: Experience With Bcvmentioning

confidence: 99%

“…A pivotal study has been completed in compliance with Good Laboratory Practice (GLP) regulations [ 16 ]. In each study, a statistically significant survival benefit was demonstrated when treatment was initiated at the onset of clinical signs of disease in the rabbits, i.e., after detection of lesions or, in the GLP study at up to 48 h after the onset of fever [ 15 , 16 ]. In the GLP study, rabbits treated with BCV immediately upon the development of fever had 100% survival; 93% of those treated 24 h or 48 h after the onset of fever survived.…”

Section: Experience With Bcvmentioning

confidence: 99%

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The Role of Brincidofovir in Preparation for a Potential Smallpox Outbreak

Foster

Parker

Lanier

2017

Viruses

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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.

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Efficacy of delayed brincidofovir treatment against a lethal rabbitpox virus challenge in New Zealand White rabbits

Cited by 33 publications

References 14 publications

Efficacy of three key antiviral drugs used to treat orthopoxvirus infections: a systematic review

Efficacy of three key antiviral drugs used to treat orthopoxvirus infections: a systematic review

Antivirals in medical biodefense

The Role of Brincidofovir in Preparation for a Potential Smallpox Outbreak

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