In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir

Abstract

Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC50) values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir demonstrated similar activity against a panel of chimeric replicons containing HCV NS5A of genotypes 1 to 6 from clinical samples. Resistance selection studies were conducted using HCV replicon cells with NS5A from genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, or 6a at a concentration of pibrentasvir that was 10- or 100-fold over its EC50 for the respective replicon. With pibrentasvir at 10-fold over the respective EC50, only a small number of colonies (0.00015 to 0.0065% of input cells) with resistance-associated amino acid substitutions were selected in replicons containing genotype 1a, 2a, or 3a NS5A, and no viable colonies were selected in replicons containing NS5A from other genotypes. With pibrentasvir at 100-fold over the respective EC50, very few colonies (0.0002% of input cells) were selected by pibrentasvir in genotype 1a replicon cells while no colonies were selected in other replicons. Pibrentasvir is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that were identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, or 93. The combination of pibrentasvir with HCV inhibitors of other classes produced synergistic inhibition of HCV replication. In summary, pibrentasvir is a next-generation HCV NS5A inhibitor with potent and pan-genotypic activity, and it maintains activity against common amino acid substitutions of HCV genotypes 1 to 6 that are known to confer resistance to currently approved NS5A inhibitors.

Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial

“…Prior studies have also reported low prevalence of both the Y93H (8.3%‐8.8%) and A30K (4.5%‐6%) polymorphisms in patients with HCV genotype 3. Moreover, as discussed, neither of these polymorphisms has a significant impact on in vitro susceptibility to PIB . In support of these data, per the US Food and Drug Administration and European Medicines Agency product use labels, GT3‐infected patients with compensated cirrhosis and/or prior treatment experience do not require viral resistance testing prior to treatment with G/P…”

“…Similarly, susceptibility to VEL and DCV is reduced by 16‐fold and 117‐fold, respectively, in the presence of A30K . In contrast, these single A30K or Y93H polymorphisms confer minimal changes to in vitro PIB susceptibility (<2.5‐fold each) …”

“…Glecaprevir (GLE) is an HCV NS3/4A protease inhibitor that has pangenotypic antiviral activity, with half‐maximal effective concentration values ≤5 nanomolar across all major HCV GTs . Pibrentasvir (PIB) is a novel pangenotypic NS5A inhibitor with half‐maximal effective concentration values of <5 pM across all major HCV GTs and a high barrier to resistance and maintains activity against single–amino acid substitutions known to confer high degrees of resistance to earlier‐generation NS5A inhibitors . Importantly, resistance‐associated NS5A substitutions in HCV GT3, such as M28T, A30K, and Y93H, each confer a <2.5‐fold increase to the half‐maximal effective concentration of PIB .…”

Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection

“…Glecaprevir (GLE, formerly ABT‐493, identified by AbbVie and Enanta), a nonstructural protein (NS) 3/4A protease inhibitor, coformulated with pibrentasvir (PIB, formerly ABT‐530), an NS5A inhibitor, is currently being evaluated as a pangenotypic regimen (G/P) for the treatment of patients with HCV infection including those with compensated cirrhosis, as well as other patient subpopulations that have been previously considered difficult to treat. Preclinical and previous clinical studies have demonstrated that this combination regimen has a high barrier to resistance and potency against common NS3 and NS5A polymorphisms . High efficacy of G/P in various patient populations over short treatment durations compared to currently recommended treatments has been demonstrated outside of Japan .…”

HCV genotype 4, 5 and 6: Distribution of viral subtypes and sustained virologic response rates in clinical trials of approved direct‐acting antiviral regimens

“…Cell culture studies demonstrated antiviral activity of each drug component against each approved GT, with data generally demonstrating consistent activity across several representative subtypes of GT 4 and 6. Although it is not feasible to capture all of the genetic diversity of GT 4 and 6 subtypes in cell culture studies and clinical trials, antiviral activity generally has been demonstrated, at minimum, across the most common representative subtypes of GT 4 and 6…”