cmx-001 and Hemorrhagic-Fever--Ebola

Ebola virus can cause severe hemorrhagic disease with high fatality rates. Currently, no specific therapeutic agent or vaccine has been approved for treatment and prevention of Ebola virus infection of humans. Although the number of Ebola cases has fallen in the last few weeks, multiple outbreaks of Ebola virus infection and the likelihood of future exposure highlight the need for development and rapid evaluation of pre- and postexposure treatments. Here, we briefly review the existing and future options for anti-Ebola therapy, based on the data coming from rare clinical reports, studies on animals, and results from in vitro models. We also project the mechanistic hypotheses of several potential drugs against Ebola virus, including small-molecule-based drugs, which are under development and being tested in animal models or in vitro using various cell types. Our paper discusses strategies toward identifying and testing anti-Ebola virus properties of known and medically approved drugs, especially those that can limit the pathological inflammatory response in Ebola patients and thereby provide protection from mortality. We underline the importance of developing combinational therapy for better treatment outcomes for Ebola patients.

Topics: Amides; Amidines; Androstenes; Animals; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antiviral Agents; Benzofurans; Cytosine; Disease Models, Animal; Disease Outbreaks; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Immune Sera; Organophosphonates; Pyrazines; RNA, Small Interfering; Stilbenes; Virus Replication

The current Ebola virus outbreak is unprecedented in its scope and international impact. Given that there are currently no approved antivirals to treat Ebola virus, there is urgency to conduct more rapid development and evaluation of Ebola antivirals. Recently, the World Health Organization identified a number of antivirals as high priority to include AVI-6002 (AVI-7537 and AVI-7539), BCX4430, brincidofovir, favipiravir, and TKM-100802. This review describes these chemically synthesized inhibitors of Ebola virus, relevant patent development and gives an update on their current status.

Topics: Adenine; Adenosine; Amides; Antiviral Agents; Cytosine; Drug Discovery; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Organophosphonates; Patents as Topic; Purine Nucleosides; Pyrazines; Pyrrolidines

The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic.. In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD.. Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients.. Pan African Clinical Trials Registry PACTR201411000939962.

Topics: Adult; Antiviral Agents; Cytosine; Ebolavirus; Female; Hemorrhagic Fever, Ebola; Humans; Liberia; Male; Middle Aged; Organophosphonates; Treatment Outcome; Young Adult

Brincidofovir (BCV) is the 3-hexadecyloxy-1-propanol (HDP) lipid conjugate of the acyclic nucleoside phosphonate cidofovir (CDV). BCV has established broad-spectrum activity against double-stranded DNA (dsDNA) viruses; however, its activity against RNA viruses has been less thoroughly evaluated. Here, we report that BCV inhibited infection of Ebola virus in multiple human cell lines. Unlike the mechanism of action for BCV against cytomegalovirus and other dsDNA viruses, phosphorylation of CDV to the diphosphate form appeared unnecessary. Instead, antiviral activity required the lipid moiety and in vitro activity against EBOV was observed for several HDP-nucleotide conjugates.

Topics: Animals; Antiviral Agents; Cell Line, Tumor; Chlorocebus aethiops; Cidofovir; Cytosine; Drug Evaluation, Preclinical; Ebolavirus; HeLa Cells; Hemorrhagic Fever, Ebola; Human Umbilical Vein Endothelial Cells; Humans; Lipids; Male; Organophosphonates; Structure-Activity Relationship; Vero Cells; Virus Replication

Topics: Africa, Western; Antiviral Agents; Clinical Trials as Topic; Cytosine; Ebola Vaccines; Ebolavirus; Epidemics; Global Health; Hemorrhagic Fever, Ebola; Humans; Organophosphonates; World Health Organization

Tragically, the outbreak of Ebola that started in West Africa in 2014 has been far more extensive and damaging than any previous outbreaks. The duration of the outbreak has, for the first time, allowed the clinical evaluation of Ebola treatments. This article discusses the designs used for two such clinical trials which have recruited patients in Liberia and Sierra Leone. General principles are outlined for trial designs intended to be deployed quickly, adapt flexibly and provide results soon enough to influence the course of the current epidemic rather than just providing evidence for use should Ebola break out again. Lessons are drawn for the conduct of clinical research in future outbreaks of infectious diseases, where the sequence of events may or may not be similar to the West African Ebola epidemic.

Topics: Antiviral Agents; Clinical Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cytosine; Disease Outbreaks; Hemorrhagic Fever, Ebola; Humans; Liberia; Organophosphonates; Randomized Controlled Trials as Topic; Research Design; Sierra Leone; Survival Rate; Treatment Outcome

Topics: Amides; Antibodies, Monoclonal; Antiviral Agents; Clinical Trials as Topic; Cytosine; Disease Outbreaks; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Organophosphonates; Pyrazines

Topics: Adenine; Adenosine; Antiviral Agents; Benzamides; Chloroquine; Communicable Diseases, Emerging; Cyclosporins; Cytosine; Dengue; Drug Approval; Drug Design; Erlotinib Hydrochloride; Hemorrhagic Fever, Ebola; Humans; Imatinib Mesylate; Indoles; Organophosphonates; Piperazines; Purine Nucleosides; Pyrimidines; Pyrroles; Pyrrolidines; Quinazolines; Sunitinib; Viruses

From 2014 to May 2015, >26 000 Ebola virus disease (EVD) cases were reported from West Africa. We present a patient with EVD who received brincidofovir and convalescent plasma. The relative contributions of supportive care, investigational therapies, and patient's immune-response on survival could not be determined. Randomized trials are needed.

Topics: Adult; Africa, Western; Alanine Transaminase; Antibodies, Viral; Antiviral Agents; Aspartate Aminotransferases; Bilirubin; Cytosine; Hemorrhagic Fever, Ebola; Humans; Immunization, Passive; Immunoglobulin G; Immunoglobulin M; Leukocyte Count; Male; Organophosphonates; Plasma; Platelet Count; Randomized Controlled Trials as Topic; RNA, Viral; Treatment Outcome; Viral Load

Topics: Adult; Biomedical Research; Child; Clinical Trials as Topic; Cooperative Behavior; Cytosine; Disaster Planning; Disease Outbreaks; Hemorrhagic Fever, Ebola; Humans; Information Dissemination; Liberia; Organophosphonates; Time Factors; Treatment Outcome; World Health Organization

Topics: Antibodies, Viral; Antiviral Agents; Cytosine; Ebolavirus; Hemorrhagic Fever, Ebola; Humans; Organophosphonates; Randomized Controlled Trials as Topic; Serum; Therapies, Investigational

Topics: Africa, Western; Amides; Anti-Infective Agents; Clinical Trials as Topic; Cytosine; France; Health Services Accessibility; Hemorrhagic Fever, Ebola; Humans; International Cooperation; Organophosphonates; Pyrazines; Societies, Medical