â€œAlthough further development of faldaprevir in combination with deleobuvir was terminated due to a strategic decision,â€ the present study provides valuable information about â€œantiviral therapies that include a combination of DAAs with a PI and a non-nucleoside thumb-pocket 1 polymerase inhibitor.â€
Faldaprevir and deleobuvir resistance-associated variants (RAVs) are more common among virologic failures than at baseline in patients with treatment emergent NS3/4A and NS5B amino-acid variants of hepatitis C virus (HCV), according to the results of a recent study. Published on the website PLOSOne, the study was conducted by Kristi Berger, PhD, of Boehringer Ingelheim Pharmaceuticals, in Ridgefield Connecticut, and colleagues.
In describing the aim of the present study, the researchers say, “The management of patients with hepatitis C virus HCV) genotype (GT)-1 infection has been transformed over recent years with the introduction of oral direct-acting antivirals (DAAs) that target essential HCV encoded viral functions.” They add that combining multiple DAAs to target different viral functions has been a focus of recent research.
“Faldaprevir is a HCV NS3/4A protease inhibitor (PI) with potent in vitro activity against HCV GT-1a and -1b, and a pharmacokinetic profile that supports once-daily (QD) dosing,” say the researchers, and continue with, “Deleobuvir is a non-nucleoside inhibitor (NNI) of HCV NS5B RNA polymerase that binds reversibly to thumb-pocket 1 of NS5B.” The combination of the two has been studied, both with and without ribavirin (RBV) in phase 2 and 3 studies.
In the present study, the researchers used samples from patients who were receiving faldaprevir and deleobuvir to analyze HCV NS3/4A and NS5B baseline polymorphisms and treatment-emergent RAVs. They say, “We aimed to assess the impact of baseline NS3/4A and NS5B polymorphisms on the virologic response to treatment, to identify and characterize treatment-emergent RAVs, and to estimate their persistence during post-treatment follow-up.”
“Pooled resistance analyses from phase 2 and 3 studies of faldaprevir/deleobuvir/RBV shows that faldaprevir RAVs at baseline are rare and response to treatment is not compromised by the common baseline NS3 polymorphisms; however, GT-1b subtype-specific polymorphisms at NS5B 499 (alanine) may reduce response to this deleobuvir-based two DAA regimen,” say the authors. They conclude, “Although further development of faldaprevir in combination with deleobuvir was terminated due to a strategic decision,” the present study provides valuable information about “antiviral therapies that include a combination of DAAs with a PI and a non-nucleoside thumb-pocket 1 polymerase inhibitor.”