摘要
Chronic infection with hepatitis C virus (HCV) is estimated to affect approximately 3% of the world's population and cause 350,000 deaths each year.Fora number of years,the standard of care has been combination therapy with recombinant alfa interferons—originally as native proteins but more recently as polyethyleneglycol-modified derivatives—and ribavirin,with the recent addition of an NS3 protease inhibitor for HCV genotype 1.However,therapeutic alfa interferons are associated with a significant burden of treatment-limiting adverse events,including musculoskeletal and influenza-like symptoms,hematologic cytopenias,autoimmune disease,fatigue,and other neurologic events.In 2003,a team at ZymoGenetics (now a fully owned subsidiary of Bristol-Myers Squibb) and a second,independent group simultaneously identified a new class of interferons—the type Ⅲ lambda interferons—with near-identical activity to the type Ⅰ alfa interferons in hepatocytes but with an unrelated and less ubiquitous receptor.Subsequent evaluation of the type Ⅲ interferon system demonstrated antiviral activity against HCV in vitro with limited activity in peripheral blood mononuclear cells and other nonhepatocyte cell types,supporting its development as a potentially better-tolerated therapy for viral hepatitis.Peginterferon lambda-1a (Lambda) is an investigational type Ⅲ therapeutic agent originally developed at ZymoGenetics that is currently in Phase 3 studies for the treatment of HCV.In this review,we describe the selection of the Lambda molecule and its preclinical and early clinical development,and how the resulting data have helped to establish the differentiated safety profile for Lambda—with fewer influenza-like and musculoskeletal symptoms and less hematologic toxicity than the alfa interferons—that was seen in later studies.
Chronic infection with hepatitis C virus (HCV) is estimated to affect approximately 3% of the world's population and cause 350,000 deaths each year.Fora number of years,the standard of care has been combination therapy with recombinant alfa interferons—originally as native proteins but more recently as polyethyleneglycol-modified derivatives—and ribavirin,with the recent addition of an NS3 protease inhibitor for HCV genotype 1.However,therapeutic alfa interferons are associated with a significant burden of treatment-limiting adverse events,including musculoskeletal and influenza-like symptoms,hematologic cytopenias,autoimmune disease,fatigue,and other neurologic events.In 2003,a team at ZymoGenetics (now a fully owned subsidiary of Bristol-Myers Squibb) and a second,independent group simultaneously identified a new class of interferons—the type Ⅲ lambda interferons—with near-identical activity to the type Ⅰ alfa interferons in hepatocytes but with an unrelated and less ubiquitous receptor.Subsequent evaluation of the type Ⅲ interferon system demonstrated antiviral activity against HCV in vitro with limited activity in peripheral blood mononuclear cells and other nonhepatocyte cell types,supporting its development as a potentially better-tolerated therapy for viral hepatitis.Peginterferon lambda-1a (Lambda) is an investigational type Ⅲ therapeutic agent originally developed at ZymoGenetics that is currently in Phase 3 studies for the treatment of HCV.In this review,we describe the selection of the Lambda molecule and its preclinical and early clinical development,and how the resulting data have helped to establish the differentiated safety profile for Lambda—with fewer influenza-like and musculoskeletal symptoms and less hematologic toxicity than the alfa interferons—that was seen in later studies.
