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 5-10 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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