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PEG-Interferon lambda (IL-29)
Overview
Cytokines play a critical role in modulating the innate and adaptive immune systems. ZymoGenetics has been at the forefront of discovering cytokines and their receptors and these efforts have resulted in a sizable therapeutic protein patent portfolio. PEG-interferon lambda (IL-29) is a novel cytokine being developed by ZymoGenetics as a potential treatment for patients infected with hepatitis C. PEG-Interferon lambda is generated in response to viral infection, signals through a receptor with a more restricted expression pattern than that used by type-I interferons alpha, beta and omega and has broad anti-viral activity. Research indicates that PEG-interferon lambda could serve as an alternative in providing therapy for viral infection.
Discovery of Interferon lambda-1
Scientists at ZymoGenetics identified from the human genomic sequence a novel family of three cytokines, designated Interleukins 28A, 28B and 29, that are distantly related to the IL-10 family and type I interferons. ZymoGenetics' researchers found that interferon lambda-1, like the type I interferons, has antiviral activity and is induced by viral infection. However, the receptor for interferon lambda-1 is much more specific in its distribution throughout the body than the receptors for type I interferons. This difference could result in fewer and more tolerable side effects. A paper by ZymoGenetics' scientists, published in the December 2002 issue of the journal Nature Immunology, further discusses PEG-interferon lambda (IL-29) and other members of this cytokine family.(1)
Rationale for PEG-Interferon lambda Therapy
PEG-interferon lambda is generated in response to viral infection. Recombinant PEG-interferon lambda shows in vitro anti-viral activity against several viruses, including hepatitis C. PEG-interferon lambda mediates anti-viral activity through a receptor that is distinct from that used by the type-I interferons and is present in fewer regions of the body. Receptors for PEG-interferon lambda are present on several important sites of viral infection, most notably the lung and liver. This suggests that PEG-interferon lambda may provide treatment for viral infection with the potential for fewer side effects than current therapies.
About Hepatitis C
The hepatitis C virus is the major cause of cirrhosis and liver cancer in the United States, and is the main reason for liver transplantation.(2) An estimated 4 million people are infected with hepatitis C in the U.S. Around 30,000 acute new infections are estimated to occur each year, of which 25-30 percent are diagnosed.(2) Of those infected with hepatitis C, approximately 80 percent have no signs or symptoms.(3) Approximately 2.7 million of these people have chronic infections with the virus.(2,3) An estimated 5-20 percent develop cirrhosis of the liver over a period of 20 to 30 years.(4) Those with hepatitis C virus-related cirrhosis have a 2-6 percent risk per year of developing hepatocellular carcinoma.(5) Of those with chronic liver disease, an estimated 1-5 percent of infected persons die each year.(3) Hepatitis C currently accounts for an estimated 8,000 10,000 deaths each year. Without effective intervention, the National Institutes of Health postulates that the number may triple in the next 10-20 years.(2)
The current standard of care for hepatitis C infection involves treatment with interferon alpha (IFN- a) and ribavirin. The majority of patients treated with interferon develop side effects early in therapy that include fever, chills and flu-like symptoms. Although these generally diminish with continued therapy, later side effects include fatigue, irritability and depression. As a result of the side effects, a reduction in interferon dosage is required in 10-40 percent of patients and, for 510 percent, treatment is discontinued.(2) For those who continue therapy, additional supportive medications and treatments are often needed.
PEG-Interferon lambda Development Plan
Based on promising preclinical data showing anti-viral activity comparable to that of IFN- a, the decision was made in mid-2005 to advance a pegylated form of interferon lambda into clinical development. ZymoGenetics submitted an Investigational New Drug application to the FDA in Q4 2006 for PEG-interferon lambda as a treatment for hepatitis C infection and has started a Phase 1a clinical trial with healthy volunteers. In 2007, the company plans to complete the Phase 1a clinical testing and initiate a Phase 1b study of PEG-interferon lambda as a treatment for hepatitis C infection.
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