Discovery Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA, 06492.
Clinical efficacy of a pegylated form of human interferon (IFN) lambda 1 (referred herein as Lambda) has been demonstrated in patients chronically infected with HCV representing genotypes 1 through 4. In these proof-of-concept studies, Lambda showed an improved safety profile compared to the pegylated form of interferon alfa (referred herein as alfa). In this report, an assessment of the in vitro antiviral activity of type III IFNs toward different HCV replicons revealed that the recombinant (r) unpegylated form of IFN lambda 1 (rIFNλ1) exerted the most robust effect while rIFNλ3 exhibited greater activity than rIFNλ2. More importantly, cross-resistance to rIFNλ1 was not observed in replicon cell lines known to have reduced susceptibility to investigational direct-acting antiviral (DAA) agents targeting the essential HCV non-structural proteins NS3, NS5A or NS5B. When combined with either rIFNα, the NS3 protease inhibitor (NS3 PI) asunaprevir (ASV), the NS5A replication complex inhibitor (NS5A RCI) daclatasvir (DCV), or the NS5B polymerase site I inhibitor (NS5B I) BMS-791325, rIFNλ1 displayed a mixture of additive and synergistic effects. In three-drug combination studies, inclusion of Lambda with ASV and DCV also yielded additive to synergistic effects. In line with these observations, it was demonstrated that combination of rIFNλ1 with one or two DAAs was superior to an IFN-free regimen in clearing HCV RNA in genotype 1a cell lines representing wild-type and NS3 protease inhibitor-resistant sequences. Overall, these data support further clinical development of Lambda as part of alternative combination treatments with DAAs for patients chronically infected with HCV.