Efficacy of therapeutic intervention with an oral ether–lipid analogue of cidofovir (CMX001) in a lethal mousepox model

Parker, Scott; Touchette, Erin; Oberle, Christina; Almond, Merrick R.; Robertson, Alice; Trost, Lawrence C.; Lampert, Bernhard; Painter, George R.; Buller, R. Mark

doi:10.1016/j.antiviral.2007.08.003

Cited by 95 publications

(87 citation statements)

References 27 publications

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“…Previous studies have shown a similar improvement in efficacy in this model when BCV is initiated in the absence of clinical signs of disease based solely on proximity to infection (so called post-exposure prophylaxis). These results are consistent with those of previous studies of BCV both in the RPXV model and in mouse models of smallpox, examining the effect of treatment initiated mid-way or later in the infection cycle (Parker et al, 2008;Quenelle et al, 2004;Rice et al, 2011a,b). Overall, early diagnosis and treatment with BCV is expected to correlate with improved patient outcome, and treatment initiated at or beyond the mid-point of disease may not be efficacious.…”

Section: Discussionsupporting

confidence: 93%

“…As was observed in the RPXV model, a single dose of 20 mg/kg, which produces plasma exposures to BCV in mice that are lower than those produced in humans given current clinical doses of BCV, provided complete protection from lethal ECTV infection when initiated as late as 4 days post-infection. Other studies demonstrated that dose regimens employing repeated BCV administration provide complete protection when initiated as late as 5 days post-infection (Parker et al, 2008(Parker et al, , 2009(Parker et al, , 2010(Parker et al, , 2012. In addition to the data supporting the efficacy of BCV in the intradermal RPXV model, these studies in a second animal model add to the weight of evidence supporting the likely efficacy of BCV for treatment of smallpox.…”

Section: Discussionmentioning

confidence: 92%

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The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: A model of smallpox disease

et al. 2015

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 92%

The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: A model of smallpox disease

et al. 2015

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“…These results show that BCV is an effective agent against multiple variola virus strains in vitro. Previous studies have demonstrated in vivo antiviral activity of BCV in numerous animal models of orthopoxvirus infection, including ectromelia virus in mice and rabbitpox virus in rabbits (12,13). Therefore, the current results support further development of BCV for the treatment of smallpox.…”

supporting

confidence: 60%

In Vitro Efficacy of Brincidofovir against Variola Virus

Olson

Smith

Foster

et al. 2014

Antimicrob Agents Chemother

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b Brincidofovir (CMX001), a lipid conjugate of the acyclic nucleotide phosphonate cidofovir, is under development for smallpox treatment using "the Animal Rule," established by the FDA in 2002. Brincidofovir reduces mortality caused by orthopoxvirus infection in animal models. Compared to cidofovir, brincidofovir has increased potency, is administered orally, and shows no evidence of nephrotoxicity. Here we report that the brincidofovir half-maximal effective concentration (EC 50 ) against five variola virus strains in vitro averaged 0.11 M and that brincidofovir was therefore nearly 100-fold more potent than cidofovir.A lthough smallpox was declared eradicated by the World Health Organization in 1980, the etiologic agent (variola virus [VARV]) remains a category A select agent (subject to select agent regulations [42CFR, part 73]) or a "Highest Priority" biological threat due to its high mortality rate and ease of transmission (1). Vaccination using a closely related live orthopoxvirus (vaccinia virus) prevents smallpox but is associated with potentially severe complications and therefore is not recommended for routine use in the absence of an immediate threat of a VARV release or smallpox outbreak. The vaccine is also contraindicated in immunocompromised individuals, including the very young or old, pregnant women, and those receiving immunosuppressive therapies (2). In the event of a VARV release, there would be a need for antiviral drugs to treat individuals exposed to or infected with smallpox.Brincidofovir(BCV,CMX001,hexadecyloxypropyl-cidofovir[HDP-CDV]), a lipid-conjugated acyclic nucleotide phosphonate, has broad-spectrum in vitro activity against double-stranded DNA viruses, including herpesviruses, adenoviruses, and poxviruses (3). BCV has completed two phase 2 clinical trials for the prevention of clinically significant cytomegalovirus infection in hematopoietic stem cell transplant patients and is currently in phase 3 trials. Simultaneously, BCV has been in development for the treatment of smallpox under the Animal Rule, which states that when developing medical countermeasures for threat agents where human challenge studies are not ethical or feasible (e.g., VARV), FDA may grant approval based on animal model studies which demonstrate that the drug is reasonably likely to have clinical benefit in humans (http: //www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM078923.pdf) (3, 4).Upon entering a cell, the lipid moiety of BCV is cleaved to release free cidofovir, which is then phosphorylated to cidofovir diphosphate (CDV-PP). CDV-PP inhibits viral DNA polymerase by serving as an alternate substrate, resulting in the inhibition of viral DNA synthesis (5-7). Among the orthopoxviruses, BCV has proven activity in animal models against vaccinia virus, rabbitpox virus (a subspecies of vaccinia), and ectromelia virus and in vitro against monkeypox virus (3). BCV has also been shown to be active against VARV in vitro (8); however, due to regulations restricting its use, these...

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“…Selection of the 20 mg/kg BCV dose for evaluation was based on the results of previous studies conducted in the lab of Mark Buller at St. Louis University (21,32; also unpublished data) as well as unpublished studies conducted by Chimerix, Inc. The regimen of three doses every 48 h (q48h) was based on the duration of disease in the model and the anticipated half-life of the active antiviral metabolite, CDV-PP, in mice and in humans as well as on the plasma pharmacokinetics of BCV in both mice and humans.…”

Section: Methodsmentioning

confidence: 99%

Postchallenge Administration of Brincidofovir Protects Healthy and Immune-Deficient Mice Reconstituted with Limited Numbers of T Cells from Lethal Challenge with IHD-J-Luc Vaccinia Virus

Zaitseva

McCullough

Cruz

et al. 2015

J Virol

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Protection from lethality by postchallenge administration of brincidofovir (BCV, CMX001) was studied in normal and immune-deficient (nude, nu/nu) BALB/c mice infected with vaccinia virus (VACV). Whole-body bioluminescence imaging was used to record total fluxes in the nasal cavity, lungs, spleen, and liver and to enumerate pox lesions on tails of mice infected via the intranasal route with 10 5 PFU of recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve (AUCs) were calculated for individual mice to assess viral loads. A three-dose regimen of 20 mg/kg BCV administered every 48 h starting either on day 1 or day 2 postchallenge protected 100% of mice. Initiating BCV treatment earlier was more efficient in reducing viral loads and in providing protection from pox lesion development. All BCV-treated mice that survived challenge were also protected from rechallenge with IHD-J-Luc or WRvFire VACV without additional treatment. In immune-deficient mice, BCV protected animals from lethality and reduced viral loads while animals were on the drug. Viral recrudescence occurred within 4 to 9 days, and mice succumbed ϳ10 to 20 days after treatment termination. Nude mice reconstituted with 10 5 T cells prior to challenge with 10 4 PFU of IHD-J-Luc and treated with BCV postchallenge survived the infection, cleared the virus from all organs, and survived rechallenge with 10 5 PFU of IHD-J-Luc VACV without additional BCV treatment. Together, these data suggest that BCV protects immunocompetent and partially T cell-reconstituted immune-deficient mice from lethality, reduces viral dissemination in organs, prevents pox lesion development, and permits generation of VACV-specific memory. IMPORTANCEMass vaccination is the primary element of the public health response to a smallpox outbreak. In addition to vaccination, however, antiviral drugs are required for individuals with uncertain exposure status to smallpox or for whom vaccination is contraindicated. Whole-body bioluminescence imaging was used to study the effect of brincidofovir (BCV) in normal and immunedeficient (nu/nu) mice infected with vaccinia virus, a model of smallpox. Postchallenge administration of 20 mg/kg BCV rescued normal and immune-deficient mice partially reconstituted with T cells from lethality and significantly reduced viral loads in organs. All BCV-treated mice that survived infection were protected from rechallenge without additional treatment. In immunedeficient mice, BCV extended survival. The data show that BCV controls viral replication at the site of challenge and reduces viral dissemination to internal organs, thus providing a shield for the developing adaptive immunity that clears the host of virus and builds virus-specific immunological memory. Smallpox was eradicated following a global immunization program using live vaccinia virus (VACV) vaccine implemented by the World Health Organization (WHO). Routine smallpox vaccination was subsequently discontinued due to a low but significant risk of severe adverse reactions. A...

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Efficacy of therapeutic intervention with an oral ether–lipid analogue of cidofovir (CMX001) in a lethal mousepox model

Cited by 95 publications

References 27 publications

The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: A model of smallpox disease

The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: A model of smallpox disease

In Vitro Efficacy of Brincidofovir against Variola Virus

Postchallenge Administration of Brincidofovir Protects Healthy and Immune-Deficient Mice Reconstituted with Limited Numbers of T Cells from Lethal Challenge with IHD-J-Luc Vaccinia Virus

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