Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.

UNLABELLED: Interferon lambda 1 (IFN-lambda1) is a type III IFN that produces intracellular responses similar to those of IFN-alpha but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open-label three-part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single-agent pegylated interferon lambda (PEG-IFN-lambda) at 1.5 or 3.0 microg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN-alpha-based treatment. Part 2 evaluated weekly doses of PEG-IFN-lambda ranging from 0.5 to 2.25 microg/kg in combination with ribavirin (RBV) for 4 weeks in treatment-relapse patients. Part 3 evaluated weekly PEG-IFN-lambda at 1.5 microg/kg in combination with RBV for 4 weeks in treatment-naive patients. Fifty-six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG-IFN-lambda dose levels (from 0.5 to 3.0 microg/kg). Two of seven treatment-naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu-like symptoms and no significant hematologic changes other than RBV-associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol-defined criteria for dose-limiting toxicity (DLT) or temporarily holding therapy with PEG-IFN-lambda. Most DLT occurred in patients with high PEG-IFN-lambda exposure. CONCLUSION: Weekly PEG-IFN-lambda with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV.

Interferon lambda as a potential new therapeutic for hepatitis C.

Interferon lambdas (IFN-lambda) are Type III interferons with biological activity, including induction of antiviral genes, similar to Type I IFNs, but signal through a distinct receptor complex. The expression pattern for the IFN-lambda receptor is more cell specific than the widely distributed IFN-alpha receptor, suggesting in vivo, IFN-lambda may have fewer side effects than IFN-alpha, such as less hematologic toxicities. A PEGylated form of IFN-lambda (PEG-rIL-29) was well tolerated in animals and did not result in hematologic toxicity. Clinical data from initial studies of PEG-rIL-29 has demonstrated antiviral effects in patients with hepatitis C without producing hematologic toxicity. These preclinical and early clinical data support PEG-rIL-29 as a potential new therapeutic agent for treatment of patients with hepatitis C.