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Genotypic and phenotypic characterization of influenza A viral variants in study participants treated with pimodivir in the phase 2b TOPAZ study

Genotypic and phenotypic characterization of influenza A viral variants in study participants... BackgroundPimodivir 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.MethodsPopulation sequencing of PB2 and neuraminidase genes, and phenotypic susceptibility testing, were performed using baseline and last virus-positive post-baseline nasal swab samples.ResultsSequencing 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: n = 3; 600 mg: n = 6; combination: n = 1; placebo: n = 0) and included positions S324, F325, S337, K376, T378, and N510. These emerging mutations were typically associated with decreased pimodivir susceptibility, but not viral breakthrough. No reduced phenotypic susceptibility was observed in the one (1.8%) participant with emerging PB2 mutations from the pimodivir plus oseltamivir group.ConclusionsParticipants 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antiviral Therapy SAGE

Genotypic and phenotypic characterization of influenza A viral variants in study participants treated with pimodivir in the phase 2b TOPAZ study

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References (23)

Publisher
SAGE
Copyright
© The Author(s) 2023
ISSN
1359-6535
eISSN
2040-2058
DOI
10.1177/13596535231174273
Publisher site
See Article on Publisher Site

Abstract

BackgroundPimodivir 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.MethodsPopulation sequencing of PB2 and neuraminidase genes, and phenotypic susceptibility testing, were performed using baseline and last virus-positive post-baseline nasal swab samples.ResultsSequencing 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: n = 3; 600 mg: n = 6; combination: n = 1; placebo: n = 0) and included positions S324, F325, S337, K376, T378, and N510. These emerging mutations were typically associated with decreased pimodivir susceptibility, but not viral breakthrough. No reduced phenotypic susceptibility was observed in the one (1.8%) participant with emerging PB2 mutations from the pimodivir plus oseltamivir group.ConclusionsParticipants 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.

Journal

Antiviral Therapy – SAGE

Published: May 18, 2023

Keywords: influenza A; pimodivir; viral variants; antiviral therapy; polymerase basic protein 2 subunit inhibitor; clinical trial; TOPAZ

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