title: Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection.
abstract: ABT-493 is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530 is an HCV NS5A inhibitor. These direct-acting antivirals (DAAs) demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistance in vitro. In this open-label dose-ranging trial, antiviral activity and safety were assessed during 3 days of monotherapy with ABT-493 or ABT-530 in treatment-naive adults with HCV genotype 1 infection, with or without compensated cirrhosis. The presence of baseline resistance-associated variants (RAVs) was also evaluated. The mean maximal decreases in HCV RNA levels from baseline were approximately 4 log10 IU/ml for all ABT-493 doses ranging from 100 mg to 700 mg and for ABT-530 doses of ≥ 40 mg. There were no meaningful differences in viral load declines for patients with versus without compensated cirrhosis. Twenty-four (50%) of the baseline samples from patients treated with ABT-493 had RAVs to NS3/4A protease inhibitors. Among 40 patients treated with ABT-530, 6 (15%) carried baseline RAVs to NS5A inhibitors. Viral load declines in patients with single baseline NS5A RAVs were similar to those in patients without RAVs. One patient harbored baseline RAVs at 3 NS5A positions and appeared to have a slightly less robust viral load decline on day 3 of monotherapy. No serious or grade 3 (severe) or higher adverse events and no clinically relevant laboratory abnormalities were observed with either compound. ABT-493 and ABT-530 demonstrated potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis. Based on these results, phase II studies assessing the combination of these DAAs for the treatment of chronic HCV infection in patients with or without compensated cirrhosis have been initiated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01995071.).
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA lawitz@txliver.com.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lawitz
authors.affiliation: eStudySite, San Diego, California, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: O'Riordan
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Armen
authors.initials: A
authors.lastname: Asatryan
authors.affiliation: Kansas City Gastroenterology & Hepatology, Kansas City, Missouri, USA.
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Freilich
authors.affiliation: Clinical Research Centers of America, Murray, Utah, USA.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Box
authors.affiliation: eStudySite, San Diego, California, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Overcash
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lovell
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Teresa I
authors.initials: TI
authors.lastname: Ng
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Campbell
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Yao
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Kort
mesh_terms: D000328:Adult; D000368:Aged; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use*; D011810:Quinoxalines / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood*; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D001562:Benzimidazoles; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D007930:Leucine; D011392:Proline; D011759:Pyrrolidines; D011810:Quinoxalines; D012367:RNA, Viral; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C096041:NS5 protein, flavivirus; C000622691:pibrentasvir; C000612853:glecaprevir