Preclinical and clinical development of pegylated interferon-lambda 1 in chronic hepatitis C.
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.
Ramos
Eleanor L
EL
ZymoGenetics, Inc., Seattle, Washington 98101, USA. ramose@zgi.com
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D007372:Interferons; D007378:Interleukins / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects; D019562:Viral Load / Q000187:drug effects; D000095022:Interferon Lambda
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a