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Background: Neuraminidase inhibitors (NAIs) reduce influenza symptoms but clear evidence of relationships between viral titer reduction and symptom alleviation is lacking. This open-label, randomized study evaluated differences in viral dynamics between NAIs, and relationships between viral dynamics and influenza symptoms (trial registration number: UMIN000012670).Methods: Patients (n = 123) aged 4-12 years with influenza A virus infection were randomized to intravenous peramivir, oral oseltamivir, inhaled zanamivir, or inhaled laninamivir. Patients received regular viral assessments of nasal discharge, at least until rapid antigen tests were negative. Time to virus clearance, based on influenza virus titer, was the primary endpoint.Results: Peramivir recipients had a significantly shorter time to virus clearance than oseltamivir recipients (adjusted p = 0.035). Comparisons between the peramivir group and other NAI groups were not significant. There were no significant inter-group differences in other clinical efficacy endpoints (time to resolution of fever, time to alleviation of symptoms). However, the peramivir group showed a smaller numerical proportion of relapses with fever or positive virus than the other groups.Conclusions: The time to virus clearance was significantly shorter with peramivir than with oseltamivir. Although no clear relationship between virus dynamics and symptoms was observed, ongoing studies should clarify the situation. [ABSTRACT FROM AUTHOR]

This work describes a set of discovery research studies of an influenza cap-dependent endonuclease (CEN) inhibitor with a carbamoyl pyridone bicycle (CAB) scaffold. Using influenza CEN inhibitory activity, antiviral activity and pharmacokinetic (PK) parameters as indices, structure activity relationships (SAR) studies were performed at the N-1 and N-3 positions on the CAB scaffold, which is a unique template to bind two metals. The hydrophobic substituent at the N-1 position is extremely important for CEN inhibitory activity and antiviral activity, and dihydrodibenzothiepine is the most promising pharmacophore. The compound (S)-13i showed potent virus titer reduction over oseltamivir phosphate in an in vivo mouse model. The CAB compound described herein served as the lead compound of baloxavir marboxil with a tricyclic scaffold, which was approved in Japan and the USA in 2018. [ABSTRACT FROM AUTHOR]

Background: We assessed the safety and effectiveness of baloxavir marboxil administration in Japanese children with influenza., Methods: This open-label study administered 1 weight-adjusted dose of baloxavir to 107 children aged 1-11 years with laboratory-confirmed, febrile influenza virus infection of ≤48 hours duration., Results: Adverse events (AEs) were reported in 34.6% of patients, most commonly vomiting (7.5%); no serious AEs or AEs causing discontinuation occurred. The median time to alleviation of influenza illness was 44.6 hours (95% confidence interval, 38.9-62.5 hours), to resolution of fever was 21.4 hours, and to sustained cessation of infectious viral shedding was 24.0 hours. However, viruses with amino acid substitutions in the viral polymerase acidic protein at position I38 (PA/I38T/M) emerged in 18 of 77 (23.4%) patients. Emergence was associated with longer infectious virus detectability (median time, 180.0 hours) and time to illness alleviation (median, 79.6 vs 42.8 hours in patients without PA/I38T/M-substituted viruses). Among patients with PA/I38T/M-substituted virus emergence, those with baseline hemagglutinin inhibition (HAI) antibody titer <40 experienced delay in time to illness alleviation (median, 85.4 vs 56.0 hours in patients with higher baseline HAI antibody titer)., Conclusions: A single, oral dose of baloxavir marboxil was well tolerated and rapidly reduced viral titers, but the common emergence of PA/I38T/M-substituted viruses warrants consideration of alternative dosing regimens in young children., Clinical Trials Registration: Japan Pharmaceutical Information Center Clinical Trials Information (Japic CTI-163417)., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: A granule formulation of baloxavir marboxil, a selective inhibitor of influenza cap-dependent endonuclease, was newly developed for children with difficulty swallowing tablets., Methods: A multicenter open-label study was conducted during the 2017-2018 influenza season to assess the safety, pharmacokinetics and clinical/virologic outcomes of single, oral, weight-based doses of baloxavir granules in Japanese children infected with influenza virus. The primary clinical endpoint was the time to illness alleviation of influenza., Results: All 33 enrolled children completed the study and received baloxavir (1 mg/kg for 12 children weighing <10 kg, 10 mg for 21 children weighing 10 to <20 kg). Detected viruses were influenza B (36.4%), A(H1N1)pdm09 (33.3%) and A(H3N2) (27.3%). Adverse events (AEs) were reported in 54.5% of children. No deaths, serious AEs or AEs leading to discontinuation were reported. The mean (SD) plasma concentrations of baloxavir acid at 24 hours post-dose were 72.8 (24.0) and 51.3 (19.3) ng/mL in the 1-mg/kg and 10-mg dose groups, respectively. The median time to illness alleviation (95% confidence interval) was 45.3 (28.5-64.1) hours. A >4-log decrease in infectious viral titer occurred on day 2 and a temporary 2-log increase on day 4. Polymerase acidic protein/I38T/M-substituted viruses were detected in 5 children infected with influenza A, but none with influenza B., Conclusions: Baloxavir granules and the weight-based dose regimen were considered to be well tolerated in children, with rapid influenza virus reduction and associated symptom alleviation. Evidence of baloxavir activity against influenza B was observed, but further data are required for confirmation.

Background: Baloxavir marboxil (baloxavir) is an antiviral drug that inhibits the viral "cap-snatching" step in virus RNA transcription initiation. In Phase 2 study, baloxavir significantly shortend the time to alleviation of symptoms (TTAS) and showed significantly greater reduction in influenza virus titer compared with placebo. This provides additional outcomes including efficacy against virus types/subtypes and pharmacokinetic/pharmacodynamic (PK/PD) analysis., Methods: Subgroup analyses by virus types/subtype were conducted for the primary and key secondary endpoints. Blood samples were collected totally at 2 to 5 points including Day 2 after baloxavir dosing. PK/PD analyses were conducted for TTAS and change in virus titer using the liner model and the E max model, respectively., Results: The median TTAS in each baloxavir dose group was significantly shorter than in the placebo group for patients with A/H1N1pdm virus, and was numerically shorter than the placebo group for patients with A/H3N2 and type B virus. Baloxavir significantly reduced virus titer within 1 day after treatment: for A/H1N1pdm, A/H3N2, and B virus, all 3 doses of baloxavir marboxil reduced virus titer on Day 2 to a greater extent than placebo. No clear PK/PD relationships were found for the TTAS, but the larger reduction in virus titer was observed in increasing C 24 ., Conclusion: These results support that baloxavir marboxil will be effective against a range of virus types/subtypes., (Copyright © 2019. Published by Elsevier B.V.)