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.)

Pharmacokinetics, Safety, and Tolerability Following Single and Multiple Doses of Pibrentasvir in a First‐in‐Human Study

“…Due to its high pangenotypic potency and resistance barrier to development of HCV variants, pibrentasvir is anticipated to achieve robust antiviral activity across all genotypes and also be efficacious in hard‐to‐treat patient populations (eg, DAA‐experienced or GT3‐infected subjects with cirrhosis) in combination with other DAAs such as glecaprevir. In HCV GT1‐infected patients with or without compensated cirrhosis, pibrentasvir displayed strong antiviral activity as evidenced by viral load decline of 3.9 to 4.2 log 10 within 3 days of receiving 40‐ to 400‐mg once‐daily regimens . In phase 2b trials with noncirrhotic GT1 through GT6 patients infected with HCV, the administration of pibrentasvir 120 mg with glecaprevir 300 mg resulted in high and sustained virologic response rates .…”

“…In HCV GT1-infected patients with or without compensated cirrhosis, pibrentasvir displayed strong antiviral activity as evidenced by viral load decline of 3.9 to 4.2 log 10 within 3 days of receiving 40-to 400-mg once-daily regimens. 17 In phase 2b trials with noncirrhotic GT1 through GT6 patients infected with HCV, the administration of pibrentasvir 120 mg with glecaprevir 300 mg resulted in high and sustained virologic response rates. 18,19 This first-in-human study characterized pibrentasvir pharmacokinetics, safety, and tolerability and provided the foundation for further clinical evaluation of pibrentasvir and rationale for dose selection in subsequent trials.…”

Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants

“…6,7,14 Two other NS3/4A PIs, asunaprevir 22 and vaniprevir, 23 have been approved in Japan. In addition, a number of next generation NS3/4A PIs are in clinical development including glecaprevir 24 and voxilaprevir 25 (Figure 1). …”

Proteases and protease inhibitors in infectious diseases

“…The remaining inhibitors namely asunaprevir, danoprevir, vaniprevir, and vedroprevir are still in various stages of clinical trials along with two more recent macrocyclic compounds, glecaprivir, and voxilaprevir (Table , Fig. ) . Developed as all‐oral once daily dosing, these would need to be co‐administered with other DAAs in order to overcome resistance barriers.…”