Article

Preclinical and clinical development of pegylated interferon-lambda 1 in chronic hepatitis C

ZymoGenetics, Inc., Seattle, Washington 98101, USA.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research (Impact Factor: 3.9). 08/2010; 30(8):591-5. DOI: 10.1089/jir.2010.0066
Source: PubMed

ABSTRACT Current treatment of chronic hepatitis C consists of pegylated interferon-alpha (PEG-IFN-alpha) in combination with ribavirin. This regimen is associated with adverse effects that can limit its use. PEG-IFN-lambda 1 (pegIFNlambda) is a novel IFN that shares many of the biological effects of IFN-alpha but may have fewer side effects due to its more selective receptor distribution. Preclinical data show that pegIFNlambda has antiviral activity against hepatitis C virus (HCV) but does not inhibit myeloid colony formation. A phase 1 study in healthy volunteers demonstrated that pegIFNlambda is well tolerated. Elevated liver enzymes resulted in a dose-limiting toxicity after a single dose of 7.5 microg/kg, the highest dose tested. A phase 1b study in genotype 1 HCV patients who either relapsed after IFN-alpha therapy or naive to therapy was initiated. Interim data from the treatment relapse subset showed viral load reductions of 2.3 to 4.0 logs when pegIFNlambda was administered weekly as a single agent with or without ribavirin for up to 4 weeks. Drug-related side effects included elevation of liver enzymes. Decreases in hemoglobin were observed only in patients receiving ribavirin. Constitutional symptoms appeared lower than historical data for PEG-IFN-alpha. These results form the basis of further development of pegIFNlambda as a novel treatment for chronic hepatitis C.

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    • "Whereas the IFNL1, -L2 and -L3 genes were described in 2003 (Kotenko et al, 2003; Sheppard et al, 2003), the IFNL4 gene was described recently and the IFNL4 gene has been inactivated in large part of the human population by a frameshift mutation (Prokunina-Olsson et al, 2013). Phase 2 of clinical trials using pegylated IFNl1 against hepatitis C virus (HCV) infection has recently been completed (Ramos, 2010), and it has now entered the phase 3 trials. IFNls are interesting pharmaceuticals, as the rather specific expression pattern of the IFNlR1 receptor should reduce the adverse effects compared to the type I IFN treatment. "
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    • "The first use of IFNλ in clinical setting has started for hepatitis C: pegylated rHu IFNλ (PEG-IFNλ) has now been evaluated in two phase 1 clinical trials [28] [29]. The initial phase 1A study was designed to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic activity of a single dose of PEG-IFNλ in healthy volunteers; a few participants developed reversible, dose-related increases in liver transaminases, but PEG-IFNλ did not induce fever, fatigue, or any overt haematological changes [28]. The phase 1B study has been conducted in patients with chronic genotype 1 HCV infection, mostly non responders to PEG-IFN/RBV therapy; PEG-IFNλ induced significant decreases in the levels of HCV, was well tolerated, and did not induce any significant haematological toxicities such as neutropenia, thrombocytopenia, or anemia [29]. "
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    • "They also discuss the differential expression of IFN-lR1 and IL-10R2 by various cell types, and provide data that shows that primary human hepatocytes express significant levels of the IFN-lR1 and IL-10R2 genes. These findings compliment the review by Eleanor Ramos (2010) in which she discusses the preclinical rationale for the use of pegylated-recombinant hIFN-l1 as a novel therapeutic agent for the treatment of chronic HCV infection. She also discusses the results of the initial Phase-1 clinical studies of IFN-l1 in patients with chronic HCV infection. "
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