title: R-1626, a specific oral NS5B polymerase inhibitor of hepatitis C virus.
abstract: Roche Holding AG is developing R-1626, an oral nucleoside inhibitor of HCV RNA polymerase. R-1626 has been demonstrated to be well absorbed and rapidly converted to the active component R-1479. The compound has demonstrated a strong capacity to inhibit HCV replication in vitro and in vivo, without the rapid development of viral resistance. After 4 weeks of treatment with R-1626 in combination with PEG-IFN plus ribavirin in treatment-naïve patients with genotype 1 HCV infection, HCV RNA could no longer be detected in approximately 74% of patients, compared with 5% of patients treated with PEG-IFN plus ribavirin alone, indicating the high potency of R-1626 to induce HCV RNA viral load reductions. R-1626 was generally well tolerated, although severe side effects of neutropenia were observed at high doses. A phase IIb clinical trial was ongoing at the time of publication to test the efficacy of R-1626 in combination with a standard or lower dose of PEG-IFN and ribavirin in HCV genotype 1-infected patients. Given its potent antiviral effect with an apparent high genetic barrier, R-1626 represents an important advancement in improving the outcome of patients with chronic HCV infection.
authors.affiliation: University of Udine, Internal Medicine, DPMSC, Medical Liver Transplant Unit, Piazzale Santa Maria della Misericordia 1, 33100 Udine, Italy. pierluigi.toniutto@uniud.it
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Toniutto
authors.forename: Carlo
authors.initials: C
authors.lastname: Fabris
authors.forename: Davide
authors.initials: D
authors.lastname: Bitetto
authors.forename: Elisa
authors.initials: E
authors.lastname: Fumolo
authors.forename: Ezio
authors.initials: E
authors.lastname: Fornasiere
authors.forename: Mario
authors.initials: M
authors.lastname: Pirisi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D015394:Molecular Structure; D009705:Nucleosides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010330:Patents as Topic; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D013329:Structure-Activity Relationship; D016896:Treatment Outcome; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000493:pharmacokinetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D011355:Prodrugs; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C530825:balapiravir