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. For a 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.