The use of miravirsen in patients with chronic HCV genotype 1 infection showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance. (Funded by Santaris Pharma; ClinicalTrials.gov number, NCT01200420.).

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Highlights d Living biobank with 80 tumor organoids was derived from treatment-naive CRC patients d Tumor organoids recapitulate histological and genetic features of original tumors d Interpatient variability in the PDO response to chemoradiation treatments d PDOs can predict locally advanced rectal cancer patient responses in the clinic

h VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m 7 GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a K D (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC 50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC 50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection. Influenza is a potentially deadly infectious disease that has imposed a substantial burden in terms of morbidity and mortality on human populations (1). Recent statistics suggest that, each year in the United States, 5% to 20% of the population becomes infected with influenza virus, with more than 200,000 hospitalizations for respiratory and heart-related complications and an annual mortality rate ranging from ϳ3,000 to 49,000 deaths (2, 3).Vaccination has become the mainstay of efforts to minimize the impact of seasonal influenza (4, 5), and while generally effective in healthy adults, it is often less effective in elderly individuals, and there have been recent examples where predictions of which viral strains to include have been inadequate (6, 7). Further, the 2009 H1N1 pandemic demonstrated that the logistics required to rapidly isolate and identify the correct strain and to produce enough vaccine worldwide was quite challenging (8-10). The continued incidence of human infection by avian influenza virus strains, namely, either the highly pathogenic H5N1 or H7N7 subtypes or the recently emerging low pathogenic H7N9 and H10N9 strains, represents an additional challenge for vaccine development strategies (11-15) Antiviral agents may be used for the prophylaxis of influenza virus infection (mainly in high-risk settings) or in a treatment modality for the reduction of illness duration. They may also provide an option for rapid deployment during a pandemic situati...

High levels of naturally occurring protease inhibitor-resistant variants were uncommon (<1% each) in HCV treatment-naive patients. TVR/PR efficiently inhibited V36M and R109K variants and contributed partial antiviral activity against the R155K variant. As new HCV agents are evaluated in clinical trials, it will be important to monitor the effect of baseline variants on sensitivity.