Phase 2b Study of Pimodivir (JNJ-63623872) as Monotherapy or in Combination With Oseltamivir for Treatment of Acute Uncomplicated Seasonal Influenza A: TOPAZ Trial

Rw, Finberg; Lanno, Riin; Anderson, David; Fleischhackl, Roman; W, van Duijnhoven; Kauffman, R. G.; Kosoglou, Teddy; Vingerhoets, Johan; Leopold, Lorant

doi:10.1093/infdis/jiy547

Cited by 92 publications

(81 citation statements)

References 11 publications

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“…Unfortunately, studies to date have not shown a benefit of TCAD over oseltamivir monotherapy [125][126][127]. Several novel antiviral compounds are in various stages of investigation, including small-molecule polymerase inhibitors such as pimodivir [128] and favipiravir [129]. A number of monoclonal and polyclonal antibodies, targeted against a variety of influenza viral proteins, are also in development [130][131][132][133].…”

Section: Treatment Of Influenzamentioning

confidence: 99%

Influenza virus-related critical illness: prevention, diagnosis, treatment

2019

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Annual seasonal influenza epidemics of variable severity result in significant morbidity and mortality in the United States (U.S.) and worldwide. In temperate climate countries, including the U.S., influenza activity peaks during the winter months. Annual influenza vaccination is recommended for all persons in the U.S. aged 6 months and older, and among those at increased risk for influenza-related complications in other parts of the world (e.g. young children, elderly). Observational studies have reported effectiveness of influenza vaccination to reduce the risks of severe disease requiring hospitalization, intensive care unit admission, and death. A diagnosis of influenza should be considered in critically ill patients admitted with complications such as exacerbation of underlying chronic comorbidities, community-acquired pneumonia, and respiratory failure during influenza season. Molecular tests are recommended for influenza testing of respiratory specimens in hospitalized patients. Antigen detection assays are not recommended in critically ill patients because of lower sensitivity; negative results of these tests should not be used to make clinical decisions, and respiratory specimens should be tested for influenza by molecular assays. Because critically ill patients with lower respiratory tract disease may have cleared influenza virus in the upper respiratory tract, but have prolonged influenza viral replication in the lower respiratory tract, an endotracheal aspirate (preferentially) or bronchoalveolar lavage fluid specimen (if collected for other diagnostic purposes) should be tested by molecular assay for detection of influenza viruses. Observational studies have reported that antiviral treatment of critically ill adult influenza patients with a neuraminidase inhibitor is associated with survival benefit. Since earlier initiation of antiviral treatment is associated with the greatest clinical benefit, standard-dose oseltamivir (75 mg twice daily in adults) for enteric administration is recommended as soon as possible as it is well absorbed in critically ill patients. Based upon observational data that suggest harms, adjunctive corticosteroid treatment is currently not recommended for children or adults hospitalized with influenza, including critically ill patients, unless clinically indicated for another reason, such as treatment of asthma or COPD exacerbation, or septic shock. A number of pharmaceutical agents are in development for treatment of severe influenza.

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Section: Treatment Of Influenzamentioning

confidence: 99%

Influenza virus-related critical illness: prevention, diagnosis, treatment

2019

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“…Pimodivir (JNJ-63623872, VX-787) received Fast Track designation by the Food and Drug Administration (FDA) in March 2017 because of its potential to address an unmet medical need in those who develop influenza A infection and are hospitalized or at high risk of related complications (Finberg et al 2019). Two phase 3 clinical trials of pimodivir are ongoing in hospitalized patients and high-risk outpatients aged 13-85 yr with influenza A infection (NCT03376321; NCT03381196).…”

Section: Pimodivirmentioning

confidence: 99%

Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Takashita

2020

Cold Spring Harb Perspect Med

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“…The key player in bunyavirus 35 transcription and genome replication is the large (L) protein with a size between 250 and 450 kDa, which contains multiple domains and functions including the viral RNA-dependent RNA polymerase (RdRp). For influenza virus, another segmented negative sense RNA virus (sNSV), small molecules targeting different functions of the polymerase complex have been clinically approved (5,6). However, in contrast to influenza viruses, whose 40 polymerase has been extensively investigated, structural and functional information about bunyavirus L proteins are scarce.…”

Section: Introductionmentioning

confidence: 99%

Structural and functional characterization of the Severe fever with thrombocytopenia syndrome virus L protein

Vogel

Thorkelsson

Quemin

et al. 2020

Preprint

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ABSTRACTThe Bunyavirales order contains several emerging viruses with high epidemic potential, including Severe fever with thrombocytopenia syndrome virus (SFTSV). The lack of medical countermeasures, such as vaccines and antivirals, is a limiting factor for the containment of any virus outbreak. To develop such antivirals a profound understanding of the viral replication process is essential. The L protein of bunyaviruses is a multi-functional and multi-domain protein performing both virus transcription and genome replication and, therefore, would be an ideal drug target. We established expression and purification procedures for the full-length L protein of SFTSV. By combining single-particle electron-cryo microscopy and X-ray crystallography, we obtained 3D models covering ∼70% of the SFTSV L protein in the apo-conformation including the polymerase core region, the endonuclease and the cap-binding domain. We compared this first L structure of the Phenuiviridae family to the structures of La Crosse peribunyavirus L protein and influenza orthomyxovirus polymerase. Together with a comprehensive biochemical characterization of the distinct functions of SFTSV L protein, this work provides a solid framework for future structural and functional studies of L protein-RNA interactions and the development of antiviral strategies against this group of emerging human pathogens.

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Phase 2b Study of Pimodivir (JNJ-63623872) as Monotherapy or in Combination With Oseltamivir for Treatment of Acute Uncomplicated Seasonal Influenza A: TOPAZ Trial

Cited by 92 publications

References 11 publications

Influenza virus-related critical illness: prevention, diagnosis, treatment

Influenza virus-related critical illness: prevention, diagnosis, treatment

Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Structural and functional characterization of the Severe fever with thrombocytopenia syndrome virus L protein

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