title: In vitro and in vivo antiviral activity and resistance profile of ombitasvir, an inhibitor of hepatitis C virus NS5A.
abstract: Ombitasvir (ABT-267) is a hepatitis C virus (HCV) NS5A inhibitor with picomolar potency, pan-genotypic activity, and 50% effective concentrations (EC50s) of 0.82 to 19.3 pM against HCV genotypes 1 to 5 and 366 pM against genotype 6a. Ombitasvir retained these levels of potency against a panel of 69 genotype 1 to 6 chimeric replicons containing the NS5A gene derived from HCV-infected patients, despite the existence of natural sequence diversity within NS5A. In vitro resistance selection identified variants that conferred resistance to ombitasvir in the HCV NS5A gene at amino acid positions 28, 30, 31, 58, and 93 in genotypes 1 to 6. Ombitasvir was evaluated in vivo in a 3-day monotherapy study in 12 HCV genotype 1-infected patients at 5, 25, 50, or 200 mg dosed once daily. All patients in the study were HCV genotype 1a infected and were without preexisting resistant variants at baseline as determined by clonal sequencing. Decreases in HCV RNA up to 3.1 log10 IU/ml were observed. Resistance-associated variants at position 28, 30, or 93 in NS5A were detected in patient samples 48 hours after the first dose. Clonal sequencing analysis indicated that wild-type virus was largely suppressed by ombitasvir during 3-day monotherapy, and at doses higher than 5 mg, resistant variant M28V was also suppressed. Ombitasvir was well tolerated at all doses, and there were no serious or severe adverse events. These data support clinical development of ombitasvir in combination with inhibitors targeting HCV NS3/4A protease (ABT-450 with ritonavir) and HCV NS5B polymerase (ABT-333, dasabuvir) for the treatment of chronic HCV genotype 1 infection. (Study M12-116 is registered at ClinicalTrials.gov under registration no. NCT01181427.).
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA preethi.krishnan@abbvie.com.
authors.forename: Preethi
authors.initials: P
authors.lastname: Krishnan
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Beyer
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Neeta
authors.initials: N
authors.lastname: Mistry
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Koev
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reisch
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: David
authors.initials: D
authors.lastname: DeGoey
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Kati
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Williams
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Wangang
authors.initials: W
authors.lastname: Xie
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Setze
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Collins
authors.affiliation: Research and Development, AbbVie, Inc., North Chicago, Illinois, USA.
authors.forename: Tami
authors.initials: T
authors.lastname: Pilot-Matias
mesh_terms: D000813:Anilides / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D002219:Carbamates / Q000627:therapeutic use*; D002460:Cell Line; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D011392:Proline; D014633:Valine
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; C586094:ombitasvir; D011392:Proline; D014633:Valine