Discussion
RSV, RSV infection, hematological abnormalities, neutropenia, PK/PD, hematologic abnormalities
ACUTE DISEASE, RSV INFECTION, VIRAL RESPIRATORY INFECTION, NEUTROPENIA
The given phase 1b and phase 2b studies evaluated the safety, PK, and efficacy of lumicitabine in infants hospitalized with RSV infection. They were undertaken following promising outcomes from preclinical studies and an RSV-A human challenge study in healthy adults [The RSV-A human challenge study results were incorporated into a population viral kinetic and PK/PD model to estimate the therapeutic effectiveness of lumicitabine, so as to guide dose selection in adult and pediatric patients [Considering that RSV is an acute disease, the dosing regimen with LD and MD in the MAD phase was designed to rapidly achieve and maintain minimal therapeutic concentrations of the lung NTP required for the inhibition of viral replication. The highest dose in the SAD phase of Study 1 (25 mg/kg) resulted in an ALS-008112 mean plasma AUCIn Study 1 and Study 2, there were no significant differences between the lumicitabine-treated groups and the placebo groups in reducing the nasal RSV viral load, the time to viral undetectability, and the resolution of RSV symptoms despite exposures in some dosing cohorts being greater than those eliciting RSV viral load reduction in the RSV-A human challenge study. The semi-mechanistic pharmacokinetic model developed in adults was extrapolated to infant populations. However, the potential for reduced drug distribution in infant lungs, or lower intracellular active triphosphate formation (not featured in the model) cannot be excluded. Higher than anticipated doses might be required to achieve clinical benefit in children. However, a study of lumicitabine in hospitalized adults with natural RSV infection failed to demonstrate RSV antiviral activity, despite exposures exceeding those in the human challenge study (NCT02935673).There are several plausible reasons for the discrepancy in the antiviral response seen between the RSV-A human challenge study in adults [Viral resistance to ALS-008112 in these studies was not observed at any of the RSV polymerase L-amino acid positions of interest in patients treated with lumicitabine [Phase 1 lumicitabine studies of healthy adult volunteers did not demonstrate hematologic abnormalities. In infants, for both Study 1 and Study 2, the accumulating safety data displayed a dose-related increase in the incidence and severity of reversible neutropenia. Except for this finding, the safety data observed in these studies were consistent with previous data of lumicitabine in adults in the human challenge study [Viral respiratory infections are reported to be associated with hematological abnormalities [Study limitations included the small sample sizes within the dose cohorts of Study 1. Furthermore, Study 2 was terminated early, impacting the ability to perform statistical analysis.In summary, lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia. However, it failed to demonstrate antiviral activity in hospitalized infants, contrary to the findings of the previous RSV-A adult human challenge study.