cmx-001 and Smallpox

cmx-001 has been researched along with Smallpox* in 17 studies

Reviews

5 review(s) available for cmx-001 and Smallpox

ArticleYear
Brincidofovir: A Novel Agent for the Treatment of Smallpox.
    The Annals of pharmacotherapy, 2023, Volume: 57, Issue:10

    This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of brincidofovir, a nucleotide analogue DNA polymerase inhibitor developed for the treatment of smallpox.. A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from inception up to December 2022, using terms. Data were limited to studies published in English language, which evaluated the efficacy and safety of brincidofovir.. Two surrogate animal models were included in the Food and Drug Administration's (FDA) decision to approve brincidofovir: ectromelia virus in mice and rabbitpox in rabbits. Phases 2 and 3 studies established safety for approval. Brincidofovir biweekly for the treatment of disseminated adenovirus disease resulted in all-cause mortality, ranging from 13.8% to 29%. In a study for cytomegalovirus prophylaxis, patients with clinically significant cytomegalovirus infection through week 24 posttransplant was 51.2% with brincidofovir and 52.3% with placebo.. Brincidofovir adds a second oral agent to treat smallpox, with a different mechanism of action than tecovirimat. In the event of a smallpox outbreak, prompt treatment will be necessary to contain its spread. Brincidofovir shows efficacy in surrogate animal models. In healthy volunteers and individuals treated, or used as prophylaxis, for cytomegalovirus or adenovirus, the primary adverse events were gastrointestinal in addition to transient hepatotoxicity. Additionally, excessive deaths were observed in hematopoietic cell transplant patients receiving it as cytomegalovirus prophylaxis, requiring a black box warning.

    Topics: Animals; Antiviral Agents; Cytomegalovirus; Cytosine; Disease Models, Animal; Hematopoietic Stem Cell Transplantation; Humans; Mice; Rabbits; Smallpox; Variola virus

2023
Benefit-risk assessment for brincidofovir for the treatment of smallpox: U.S. Food and Drug Administration's Evaluation.
    Antiviral research, 2021, Volume: 195

    The development and approval of brincidofovir for the treatment of smallpox, a disease that was eradicated from the world over 40 years ago, has resulted in the second antiviral approved via the Medical Countermeasure Initiative (MCMi) to combat this disease. Approval of brincidofovir required a unique regulatory approach based on the FDA Animal Rule, and development was supported by many years of research and collaboration among academic investigators, the pharmaceutical industry and multiple government agencies. This article summarizes the FDA regulatory pathway and describes the challenges involved.

    Topics: Animals; Antiviral Agents; Cytosine; Disease Eradication; Disease Models, Animal; Drug Approval; Humans; Organophosphonates; Risk Assessment; Smallpox; Treatment Outcome; United States; United States Food and Drug Administration

2021
Drug Development against Smallpox: Present and Future.
    Antimicrobial agents and chemotherapy, 2020, 03-24, Volume: 64, Issue:4

    Forty years after the last endemic smallpox case, variola virus (VARV) is still considered a major threat to humans due to its possible use as a bioterrorism agent. For many years, the risk of disease reemergence was thought to solely be through deliberate misuse of VARV strains kept in clandestine laboratories. However, recent experiments using synthetic biology have proven the feasibility of recreating a poxvirus

    Topics: Animals; Antiviral Agents; Benzamides; Biological Warfare Agents; Biomedical Research; Cytosine; Disease Models, Animal; Drug Discovery; Isoindoles; Organophosphonates; Smallpox; Variola virus

2020
Efficacy of CMX001 as a prophylactic and presymptomatic antiviral agent in New Zealand white rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans.
    Viruses, 2011, Volume: 3, Issue:2

    CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox virus, a zoonotic disease of Africa, and adverse reactions to smallpox virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the rabbitpox virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination.

    Topics: Animals; Antiviral Agents; Bioterrorism; Cytosine; Disease Models, Animal; Disease Transmission, Infectious; Humans; Mpox (monkeypox); Organophosphonates; Rabbits; Smallpox; Smallpox Vaccine; Vaccinia virus

2011
Efficacy of CMX001 as a post exposure antiviral in New Zealand White rabbits infected with rabbitpox virus, a model for orthopoxvirus infections of humans.
    Viruses, 2011, Volume: 3, Issue:1

    CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Previously, we demonstrated the efficacy of CMX001 in protecting New Zealand White rabbits from mortality following intradermal infection with rabbitpox virus as a model for smallpox, monkeypox and for treatment of adverse reactions to smallpox vaccination. Here we extend these studies by exploring different dosing regimens and performing randomized, blinded, placebo-controlled studies. In addition, because rabbitpox virus can be transmitted via naturally generated aerosols (animal to animal transmission), we report on studies to test the efficacy of CMX001 in protecting rabbits from lethal rabbitpox virus disease when infection occurs by animal to animal transmission. In all cases, CMX001 treatment was initiated at the onset of observable lesions in the ears to model the use of CMX001 as a treatment for symptomatic smallpox. The results demonstrate that CMX001 is an effective treatment for symptomatic rabbitpox virus infection. The rabbitpox model has key similarities to human smallpox including an incubation period, generalized systemic disease, the occurrence of lesions which may be used as a trigger for initiating therapy, and natural animal to animal spread, making it an appropriate model.

    Topics: Animals; Antiviral Agents; Cytosine; Disease Models, Animal; Disease Transmission, Infectious; Dose-Response Relationship, Drug; Humans; Mpox (monkeypox); Organophosphonates; Rabbits; Random Allocation; Smallpox; Vaccinia virus

2011

Trials

1 trial(s) available for cmx-001 and Smallpox

ArticleYear
Short-term clinical safety profile of brincidofovir: A favorable benefit-risk proposition in the treatment of smallpox.
    Antiviral research, 2017, Volume: 143

    Brincidofovir (BCV, CMX001) is an orally available, long-acting, broad-spectrum antiviral that has been evaluated in healthy subjects in Phase I studies and in hematopoietic cell transplant recipients and other immunocompromised patients in Phase II/III clinical trials for the prevention and treatment of cytomegalovirus and adenovirus infections. BCV has also shown in vitro activity against orthopoxviruses such as variola (smallpox) virus, and is under advanced development as a treatment for smallpox under the US FDA's 'Animal Rule'. The anticipated treatment regimen for smallpox is a total weekly dose of 200 mg administered orally for 3 consecutive weeks. To assess the benefit-to-risk profile of BCV for the treatment of smallpox, we evaluated short-term safety data associated with comparable doses from Phase I studies and from adult and pediatric subjects in the cytomegalovirus and adenovirus clinical programs. When administered at doses and durations similar to that proposed for the treatment of smallpox, BCV was generally well tolerated in both adults and pediatric subjects. The most common adverse events were mild gastrointestinal events and asymptomatic, transient, and reversible elevations in serum transaminases. The data presented herein indicate a favorable safety profile for BCV for the treatment of smallpox, and support its continued development for this indication.

    Topics: Adenoviridae; Adolescent; Adult; Animals; Antiviral Agents; Cytomegalovirus; Cytosine; Disease Models, Animal; Double-Blind Method; Drug Administration Schedule; Humans; Middle Aged; Organophosphonates; Orthopoxvirus; Safety; Smallpox; Young Adult

2017

Other Studies

11 other study(ies) available for cmx-001 and Smallpox

ArticleYear
Identification of
    Microbiology spectrum, 2023, 08-17, Volume: 11, Issue:4

    Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were reported globally, with evidence of person-to-person transmission. Because of this, the World Health Organization (WHO) declared the MPXV outbreak a public health emergency of international concern. The supply of MPXV vaccines is limited, and only two antivirals, tecovirimat and brincidofovir, approved by the U.S. Food and Drug Administration (FDA) for the treatment of smallpox, are currently available for the treatment of MPXV infection. Here, we evaluated 19 compounds previously shown to inhibit different RNA viruses for their ability to inhibit orthopoxvirus infections. We first used recombinant vaccinia virus (rVACV) expressing fluorescence (mScarlet or green fluorescent protein [GFP]) and luciferase (Nluc) reporter genes to identify compounds with antiorthopoxvirus activity. Seven compounds from the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, pyrazofurin, mycophenolate mofetil, azaribine, and brequinar) and six compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) showed inhibitory activity against rVACV. Notably, the anti-VACV activity of some of the compounds in the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, mycophenolate mofetil, and brequinar) and all the compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) were confirmed with MPXV, demonstrating their inhibitory activity

    Topics: Antimycin A; Antiviral Agents; Humans; Monensin; Monkeypox virus; Mpox (monkeypox); Mycophenolic Acid; Rotenone; Smallpox; Valinomycin

2023
A human recombinant analogue to plasma-derived vaccinia immunoglobulin prophylactically and therapeutically protects against lethal orthopoxvirus challenge.
    Antiviral research, 2021, Volume: 195

    Orthopoxviruses such as variola and monkeypox viruses continue to threaten the human population. Monkeypox virus is endemic in central and western Africa and outbreaks have reached as far as the U.S. Although variola virus, the etiologic agent of smallpox, has been eradicated by a successful vaccination program, official and likely clandestine stocks of the virus exist. Moreover, studies with ectromelia virus (the etiological agent of mousepox) have revealed that IL-4 recombinant viruses are significantly more virulent than wild-type viruses even in mice treated with vaccines and/or antivirals. For these reasons, it is critical that antiviral modalities are developed to treat these viruses should outbreaks, or deliberate dissemination, occur. Currently, 2 antivirals (brincidofovir and tecovirimat) are in the U.S. stockpile allowing for emergency use of the drugs to treat smallpox. Both antivirals have advantages and disadvantages in a clinical and emergency setting. Here we report on the efficacy of a recombinant immunoglobulin (rVIG) that demonstrated efficacy against several orthopoxviruses in vitro and in vivo in both a prophylactic and therapeutic fashion. A single intraperitoneal injection of rVIG significantly protected mice when given up to 14 days before or as late as 6 days post challenge. Moreover, rVIG reduced morbidity, as measured by weight-change, as well as several previously established biomarkers of disease. In rVIG treated mice, we found that vDNA levels in blood were significantly reduced, as was ALT (a marker of liver damage) and infectious virus levels in the liver. No apparent adverse events were observed in rVIG treated mice, suggesting the immunoglobulin is well tolerated. These findings suggest that recombinant immunoglobulins could be candidates for further evaluation and possible licensure under the FDA Animal Rule.

    Topics: Animals; Antiviral Agents; Benzamides; Cell Line; Chlorocebus aethiops; Cytosine; Female; Humans; Immunoglobulins; Isoindoles; Mice; Mice, Inbred BALB C; Organophosphonates; Orthopoxvirus; Smallpox; Smallpox Vaccine; Vaccines, DNA; Vaccinia

2021
The spectre of smallpox lingers.
    Nature, 2018, Volume: 560, Issue:7718

    Topics: Animals; Benzamides; Cytosine; Disease Eradication; Disease Models, Animal; Disease Reservoirs; Drug Approval; Female; History, 20th Century; History, 21st Century; Humans; Isoindoles; Organophosphonates; Rabbits; Smallpox; Smallpox Vaccine; Synthetic Biology; United States; United States Food and Drug Administration

2018
Efficacy of delayed brincidofovir treatment against a lethal rabbitpox virus challenge in New Zealand White rabbits.
    Antiviral research, 2017, Volume: 143

    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.

    Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Antiviral Agents; Body Temperature; Body Weight; Cytosine; Disease Models, Animal; Double-Blind Method; Organophosphonates; Poxviridae Infections; Rabbits; Smallpox; Survival Rate; Treatment Outcome; Vaccination; Vaccinia; Vaccinia virus; Variola virus; Viral Load

2017
The Role of Brincidofovir in Preparation for a Potential Smallpox Outbreak.
    Viruses, 2017, 10-30, Volume: 9, Issue:11

    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.

    Topics: Animals; Antiviral Agents; Benzamides; Biological Warfare Agents; Cytosine; Databases, Pharmaceutical; Disease Outbreaks; Drug Resistance, Viral; Drug Therapy, Combination; Humans; Isoindoles; Models, Animal; Organophosphonates; Smallpox; Variola virus

2017
Buccal viral DNA as a trigger for brincidofovir therapy in the mousepox model of smallpox.
    Antiviral research, 2017, Volume: 139

    Orthopoxviruses continue to pose a significant threat to the population as potential agents of bioterrorism. An intentional release of natural or engineered variola virus (VARV) or monkeypox viruses would cause mortality and morbidity in the target population. To address this, antivirals have been developed and evaluated in animal models of smallpox and monkeypox. One such antiviral, brincidofovir (BCV, previously CMX001), has demonstrated high levels of efficacy against orthopoxviruses in animal models and is currently under clinical evaluation for prevention and treatment of diseases caused by cytomegaloviruses and adenoviruses. In this study we use the mousepox model of smallpox to evaluate the relationship between the magnitude of the infectious virus dose and an efficacious BCV therapy outcome when treatment is initiated concomitant with detection of ectromelia virus viral DNA (vDNA) in mouse buccal swabs. We found that vDNA could be detected in buccal swabs of some, but not all infected mice over a range of challenge doses by day 3 or 4 postexposure, when initiation of BCV treatment was efficacious, suggesting that detection of vDNA in buccal swabs could be used as a trigger to initiate BCV treatment of an entire potentially exposed population. However, buccal swabs of some mice did not become positive until 5 days postexposure, when initiation of BCV therapy failed to protect mice that received high doses of virus. And finally, the data suggest that the therapeutic window for efficacious BCV treatment decreases as the virus infectious dose increases. Extrapolating these findings to VARV, the data suggest that treatment should be initiated as soon as possible after exposure and not rely on a diagnostic tool such as the measurement of vDNA in buccal cavity swabs; however, consideration should be given to the fact that the behavior/disease-course of VARV in humans is different from that of ectromelia virus in the mouse.

    Topics: Animals; Antiviral Agents; Cytosine; Disease Models, Animal; DNA, Viral; Ectromelia virus; Ectromelia, Infectious; Mice; Mouth Mucosa; Organophosphonates; Orthopoxvirus; Smallpox

2017
The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: a model of smallpox disease.
    Antiviral research, 2015, Volume: 117

    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.

    Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Antiviral Agents; Cidofovir; Cytosine; Disease Models, Animal; Humans; Injections, Intradermal; Organophosphonates; Rabbits; Random Allocation; Smallpox; Vaccinia; Vaccinia virus; Variola virus

2015
In vitro efficacy of brincidofovir against variola virus.
    Antimicrobial agents and chemotherapy, 2014, Volume: 58, Issue:9

    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 (EC50) against five variola virus strains in vitro averaged 0.11 μM and that brincidofovir was therefore nearly 100-fold more potent than cidofovir.

    Topics: Animals; Antiviral Agents; Cell Line; Chlorocebus aethiops; Cidofovir; Cytosine; Disease Models, Animal; DNA, Viral; Humans; In Vitro Techniques; Microbial Sensitivity Tests; Organophosphonates; Smallpox; Variola virus

2014
Evaluation of disease and viral biomarkers as triggers for therapeutic intervention in respiratory mousepox - an animal model of smallpox.
    Antiviral research, 2012, Volume: 94, Issue:1

    The human population is currently faced with the potential use of natural or recombinant variola and monkeypox viruses as biological weapons. Furthermore, the emergence of human monkeypox in Africa and its expanding environs poses a significant natural threat. Such occurrences would require therapeutic and prophylactic intervention with antivirals to minimize morbidity and mortality of exposed populations. Two orally-bioavailable antivirals are currently in clinical trials; namely CMX001, an ether-lipid analog of cidofovir with activity at the DNA replication stage and ST-246, a novel viral egress inhibitor. Both of these drugs have previously been evaluated in the ectromelia/mousepox system; however, the trigger for intervention was not linked to a disease biomarker or a specific marker of virus replication. In this study we used lethal, intranasal, ectromelia virus infections of C57BL/6 and hairless SKH1 mice to model human disease and evaluate exanthematous rash (rash) as an indicator to initiate antiviral treatment. We show that significant protection can be provided to C57BL/6 mice by CMX001 or ST-246 when therapy is initiated on day 6 post infection or earlier. We also show that significant protection can be provided to SKH1 mice treated with CMX001 at day 3 post infection or earlier, but this is four or more days before detection of rash (ST-246 not tested). Although in this model rash could not be used as a treatment trigger, viral DNA was detected in blood by day 4 post infection and in the oropharyngeal secretions (saliva) by day 2-3 post infection - thus providing robust and specific markers of virus replication for therapy initiation. These findings are discussed in the context of current respiratory challenge animal models in use for the evaluation of poxvirus antivirals.

    Topics: Animals; Benzamides; Biomarkers, Pharmacological; Cell Line; Cytosine; Disease Models, Animal; Drug Evaluation, Preclinical; Ectromelia virus; Ectromelia, Infectious; Female; Humans; Isoindoles; Mice; Mice, Hairless; Mice, Inbred C57BL; Monkeypox virus; Organophosphonates; Smallpox; Variola virus; Virus Replication

2012
Biodefence since 9/11: The price of protection.
    Nature, 2011, Sep-07, Volume: 477, Issue:7363

    Topics: Animals; Antiviral Agents; Biomedical Research; Bioterrorism; Budgets; Cytosine; Disease Models, Animal; Humans; Male; Organophosphonates; Security Measures; September 11 Terrorist Attacks; Smallpox; Tularemia; United States; Vaccines; Young Adult

2011
Scientific report: highlights of 24th ICAR, 8-11 May 2011, Sofia, Bulgaria.
    Antiviral chemistry & chemotherapy, 2011, Oct-07, Volume: 22, Issue:2

    The 24th ICAR meeting was held in Sofia, Bulgaria, 8-11 May 2011. This report summarizes the presentations by the ICAR award winners, Earl Kern and Brian Gowen; the keynote address by Albert (ADME) Osterhaus; the Plenary lectures by Raina Fichorova, Ralf Bartenschlager and Esteban Domingo; the invited speakers for the symposia; and a few of those by contributors. This report aims to reflect the diversity of topics across different disciplines (chemistry to biology) discussed at ICAR: old viruses (smallpox), emerging viruses (SARS, new strains of influenza and flaviviruses), problematic viruses (HIV and HCV), sporadic viruses (arenaviruses), neglected viruses (enteroviruses), new research targets (for HCV) and new approaches (lethal mutagenesis). There were timely reports on promising compounds against adenoviruses, cytomegalovirus, HCV and HIV in clinical trials.This conference illuminated the constantly evolving field of antiviral chemotherapy by providing a forum to present and discuss new antiviral compounds, new uses for old compounds and exciting clinical results. This ICAR was a fitting testament to the 'father of antiviral chemotherapy', Bill Prusoff, who died aged 90 in April 2011.

    Topics: Adenine; Animals; Antiviral Agents; Arenavirus; Chemistry, Pharmaceutical; Communicable Diseases, Emerging; Cytosine; Flavivirus; Hepacivirus; HIV Seropositivity; Humans; Organophosphonates; Prodrugs; Smallpox; Tenofovir; Virus Replication

2011