vx-787 and Influenza--Human

The influenza virus RNA-dependent RNA polymerase is highly conserved among influenza A, B, C, and D viruses. It comprises three subunits: polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA) in influenza A and B viruses or polymerase 3 protein (P3) in influenza C and D viruses. Because this polymerase is essential for influenza virus replication, it has been considered as a target for antiviral agents. Recently, several polymerase inhibitors that target each subunit have been developed. This review discusses the mechanism of action, antiviral activity, and emergence of resistance to three inhibitors approved for the treatment of influenza or in late-phase clinical trials: the PB1 inhibitor favipiravir, the PB2 inhibitor pimodivir, and the PA inhibitor baloxavir marboxil.

Topics: Amides; Antiviral Agents; Dibenzothiepins; Drug Resistance, Viral; Humans; Influenza, Human; Morpholines; Orthomyxoviridae; Pyrazines; Pyridines; Pyridones; Pyrimidines; Pyrroles; RNA-Dependent RNA Polymerase; Triazines; Virus Replication

Influenza represents a significant treatment burden to critical care services. A variety of treatment strategies exist, with more and more therapeutic avenues opening up as research progresses. We examined both pharmacological and supportive treatment strategies currently available to see how they might be applied in an ICU setting.. Supportive care in Influenza centres around optimizing respiratory failure, particularly through well established and recognized ventilatory strategies. Noninvasive ventilation and high-flow nasal oxygen may have a limited role in selected patients under carefully monitored circumstances. Drug therapy exerts only a modest clinical effect and has been poorly studied in the critically ill, though there is some evidence to support the use of neuraminidase inhibitors (NAI) - particularly oseltamivir - as early as possible in this cohort. Newer agents have failed to demonstrate superiority over NAIs but may be useful options if the patient fails to respond or should resistant influenza strains emerge. Steroid therapy, in the absence of another indication, must be recommended against given the repeated trend towards increased mortality in this group.. Influenza management is an evolving field of significant interest to any critical care provider. Currently, good respiratory supportive care and early enteral oseltamivir are the best supported treatment strategies. Further study in the intensive care setting will be needed before the use of novel agents can be recommended.

Topics: Adrenal Cortex Hormones; Amides; Antiviral Agents; Critical Care; Critical Illness; Dibenzothiepins; Enzyme Inhibitors; Humans; Influenza, Human; Morpholines; Neuraminidase; Oseltamivir; Pyrazines; Pyridines; Pyridones; Pyrimidines; Pyrroles; Respiration, Artificial; Triazines; Zanamivir

Pimodivir is a first-in-class polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A polymerase complex. The randomized double-blinded placebo-controlled phase 2b TOPAZ study demonstrated antiviral activity and safety of twice daily pimodivir alone (300 mg, 600 mg) or in combination with oseltamivir (pimodivir 600 mg, oseltamivir 75 mg) in adult study participants with acute uncomplicated influenza A. The detailed genotypic and phenotypic characterization of viral variants observed in this study are reported.. Population sequencing of PB2 and neuraminidase genes, and phenotypic susceptibility testing, were performed using baseline and last virus-positive post-baseline nasal swab samples.. Sequencing of baseline samples in 206 of 223 (92.4%) randomized study participants with confirmed influenza A infection identified no polymorphisms at any predefined PB2 positions of interest for pimodivir and no phenotypic reduced susceptibility to pimodivir was observed. Post-baseline sequencing data for 105/223 (47.1%) participants identified emergence of PB2 mutations at amino acid positions of interest in 10 (9.5%) participants (pimodivir 300 mg:. Participants with acute uncomplicated influenza A treated with pimodivir in the TOPAZ study infrequently developed reduced susceptibility to pimodivir and combining pimodivir with oseltamivir further decreased the risk of reduced susceptibility development.

Topics: Adult; Antiviral Agents; Genotype; Humans; Influenza A virus; Influenza, Human; Oseltamivir

Both the elderly and individuals with comorbidities are at increased risk of developing influenza-related complications. Novel influenza antivirals are required, given limitations of current drugs (eg, resistance emergence and poor efficacy). Pimodivir is a first-in-class antiviral for influenza A under development for these patients.. Hospitalized patients with influenza A infection were randomized 2:1 to receive pimodivir 600 mg plus oseltamivir 75 mg or placebo plus oseltamivir 75 mg twice daily for 7 days in this phase 2b study. The primary objective was to compare pimodivir pharmacokinetics in elderly (aged 65-85 years) versus nonelderly adults (aged 18-64 years). Secondary end points included time to patient-reported symptom resolution.. Pimodivir pharmacokinetic parameters in nonelderly and elderly patients were similar. Time to influenza symptom resolution was numerically shorter with pimodivir (72.45 hours) than placebo (94.15 hours). There was a lower incidence of influenza-related complications in the pimodivir group (7.9%) versus placebo group (15.6%). Treatment was generally well tolerated.. No apparent relationship was observed between pimodivir pharmacokinetics and age. Our data demonstrate the need for a larger study of pimodivir in addition to oseltamivir to test whether it results in a clinically significant decrease in time-to-influenza-symptom alleviation and/or the frequency of influenza complications.. NCT02532283.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Humans; Influenza, Human; Middle Aged; Oseltamivir; Pyridines; Pyrroles; Treatment Outcome; Young Adult

Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A.. In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated.. Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription-polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, -3.6 day*log10 copies/mL [95% confidence interval {CI}, -7.1 to -0.1]; 600 mg group, -4.5 [95%CI -8.0 to -1.0]; and combination group, -8.6 [95% CI, -12.0 to -5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea.. Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development.. NCT02342249, 2014-004068-39, and CR107745.

Topics: Acute Disease; Adult; Antiviral Agents; Diarrhea; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Early Termination of Clinical Trials; Female; Humans; Influenza A virus; Influenza, Human; Male; Middle Aged; Oseltamivir; Pyridines; Pyrimidines; Pyrroles; Time Factors; Viral Load; Viral Proteins; Virus Shedding

Influenza A viruses possess a high antigenic shift, and the approved anti-influenza drugs are extremely limited, which makes the development of novel anti-influenza drugs for the clinical treatment and prevention of influenza outbreaks imperative. Herein, we report a series of novel aryl benzoyl hydrazide analogs as potent anti-influenza agents. Particularly, analogs

Topics: Animals; Antiviral Agents; Humans; Hydrazines; Influenza A virus; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza, Human; Mice; RNA-Dependent RNA Polymerase; Virus Replication

Pimodivir exerts an antiviral effect on the early stages of influenza A virus replication by inhibiting the cap-binding function of polymerase basic protein 2 (PB2). In this study, we used a combination of sequence analysis and phenotypic methods to evaluate pimodivir susceptibility of influenza A viruses collected from humans and other hosts. Screening PB2 sequences for substitutions previously associated with reduced pimodivir susceptibility revealed a very low frequency among seasonal viruses circulating in the U.S. during 2015-2020 (<0.03%; 3/11,934) and among non-seasonal viruses collected in various countries during the same period (0.2%; 18/8971). Pimodivir potently inhibited virus replication in two assays, a single-cycle HINT and a multi-cycle FRA, with IC

Topics: Animals; Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Influenza A virus; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H7N9 Subtype; Influenza, Human; Microbial Sensitivity Tests; Orthomyxoviridae Infections; Pyridines; Pyrimidines; Pyrroles; RNA-Dependent RNA Polymerase; Viral Proteins; Virus Replication

With the aim to identify novel influenza PB2 inhibitors with high potency and excellent pharmacokinetic parameters, we have designed and synthesized two new series of pyrimidine-fused heterocycle derivatives based on two generations of co-crystal structures. Docking studies with the newly disclosed PDB structure guided the second round of rational design and led to the discovery of 25m, 25o and 25p as representative compounds with improved potency (EC

Topics: Animals; Antiviral Agents; Drug Design; Heterocyclic Compounds; Humans; Influenza A virus; Influenza, Human; Mice; Molecular Docking Simulation; Orthomyxoviridae Infections; Pyrimidines; Viral Proteins

Exploration of the chemical space of known influenza polymerase PB2 inhibitor Pimodivir, was performed by our group. We synthesized and identified compounds 16a and 16b, two novel thienopyrimidine derivatives displaying anti-influenza A activity in the single digit nanomolar range in cell culture. Binding of these unique compounds in the influenza polymerase PB2 pocket was also determined using molecular modeling.

Topics: A549 Cells; Amino Acid Sequence; Animals; Antiviral Agents; Drug Discovery; Humans; Influenza A virus; Influenza, Human; Models, Molecular; Molecular Structure; Protein Binding; Pyridines; Pyrimidines; Pyrroles; RNA-Dependent RNA Polymerase; Structure-Activity Relationship; Viral Proteins; Virus Replication