DALLAS, TX -- November 8, 1999 -- In the largest prospective study
to include only hepatitis C patients with cirrhosis, Pegasys™
(peginterferon alfa-2a) may achieve a sustained response rate
nearly five times higher than standard interferon. This data,
presented at the 50th annual meeting of the American Association
for the Study of Liver Diseases (AASLD), comes at a time when liver
failure due to chronic hepatitis C and related cirrhosis is the
leading cause of liver transplants in the United States.
The data from a randomized, controlled, multicenter Phase II/III
trial found that in an intent-to-treat analysis, 29 percent (n=87)
of cirrhotic patients treated with 180 mcg. of once-weekly Pegasys,
an investigational interferon alfa-2a, experienced a sustained
response of undetectable levels of hepatitis C virus (HCV) compared
to 6 percent of patients (n=88) treated with currently marketed
interferon. Sustained response is measured at 24 weeks following a
treatment period of 48 weeks. The presence of HCV was measured by
the Roche Diagnostics Amplicor® HCV Test V2.0.
"This study is an important step forward in finding a treatment
that provides a higher response rate than currently available
interferons for hepatitis C patients with cirrhosis," said Dr. E.
Jenny Heathcote, Professor of medicine, University of Toronto, and
gastroenterologist, University Health Network, Toronto Western
Hospital, in Toronto, ON.
The Phase II/III cirrhotic study followed 271 HCV-infected
patients with cirrhosis for a total of 72 weeks -- 48 weeks of
treatment followed by a 24-week post-treatment follow-up. Patients
were randomized to one of two groups to receive once-weekly doses
of 90 mcg. or 180 mcg. of Pegasys or three million international
units (MIU) of interferon three times per week.
In the Phase II/III cirrhotic study, adverse events with Pegasys
were similar to those seen with traditional interferon regimens,
such as fatigue, headache, myalgia/arthralgia, flu-like symptoms,
nausea/vomiting, injection site reactions, fever, chills, diarrhea,
partial alopecia, abdominal pain, depression, irritability,
insomnia, dizziness and anorexia. Dose modification was required
for thrombocytopenia in six percent, 18 percent and 19 percent and
for neutropenia in 14 percent, nine percent and 11 percent of
patients in the interferon, 90 mcg. and 180 mcg. Pegasys groups
Cirrhosis of the liver can permanently injure and scar the
liver, decreasing the amount of normal functioning liver tissue.
Moreover, the scar tissue interferes with the flow of blood through
the liver, further interfering with normal liver function.
Approximately 20 percent of people with hepatitis C-at least
780,000 Americans-are expected to develop cirrhosis within 10 to 20
Earlier this year, results from a Phase II study of 155
non-cirrhotic, hepatitis C-infected patients were presented during
Digestive Disease Week.
The study found that 36 percent of patients treated with 180
mcg. of Pegasys experienced a sustained response of undetectable
levels of hepatitis C.
Adverse events experienced during the Phase II study with
Pegasys appear to be similar to those seen with traditional
Sizing Up the "PEG" in Pegasys
Pegylation is the process of attaching one or more chains of
polyethylene glycol (also known as PEG) to another molecule. In
Pegasys, a large, branched, mobile PEG is covalently bound to the
interferon alfa-2a molecule and provides a selectively protective
barrier. Pharmacokinetic behavior depends on the length of the PEG
and the structure of the link between the PEG moiety and the
protein. Researchers believe the PEG creates a barrier that shields
the interferon alfa-2a from being eliminated from the body too
rapidly and maintains its ability to suppress the hepatitis C
The large, branched PEG in Pegasys is designed to increase
solubility and duration of the virus' exposure to the drug, which
may account for the elimination of large "peak-to-trough"
fluctuations experienced with standard interferon. As a result, the
increased sustained response rate and tolerability of Pegasys may
be enhanced, leading to constant viral suppression and a reduction
in the incidence and severity of peak-related side effects.
The high molecular weight (40 kilodalton) branched PEG in
Pegasys-is believed to provide sustained pegylated interferon
alfa-2a exposure at clinically effective levels. Results of a
pharmacokinetics (PK) study, which was also presented at the AASLD
meeting, revealed that sustained delivery of Pegasys occurs with
maximum concentrations reached at 80 hours, with substantial
concentrations seen 3 to 8 hours after dosing. The study suggests
that a PEG that weighs 40 kilodaltons (40k) results in sustained
concentrations throughout the dosing interval, and reduced
clearance of Pegasys versus standard interferon. Administered once
weekly, the therapeutic concentrations of Pegasys last throughout
one full week. In contrast, interferons with smaller PEGs are
excreted quickly by the kidneys, requiring more frequent dosing,
according to earlier Roche studies.
First Results on Pegasys with Ribavirin
Results of a study to evaluate Pegasys 180 mcg. in combination with
ribavirin 1000-1200mg, may indicate positive antiviral activity and
good tolerability. In this Phase II pilot study also presented at
AASLD, a once-weekly dose of Pegasys was administered to 20
patients with chronic hepatitis C, in combination with 1000-1200 mg
oral ribavirin twice daily, for 24 to 48 weeks, followed by a
24-week post-treatment follow-up. At week 48 of the study, 70
percent of patients (14/20) had undetectable levels (less than 100
copies/mL) of HCV in their blood. Adverse events with
Pegasys/ribavirin combination therapy were mild to moderate in
severity. Four patients experienced severe adverse events. Larger
studies to further evaluate the use of Pegasys in combination with
ribavirin are ongoing.
Ribavirin therapy is contraindicated in women who are pregnant
and in the male partners of women who are pregnant. Extreme care
must be taken to avoid pregnancy during therapy and for six months
after completion of treatment in female patients, and in female
partners of male patients who are taking combination
ribavirin/interferon therapy. Women of childbearing potential and
men must use two reliable forms of effective contraception during
treatment and during the six-month post-treatment follow-up period.
Significant teratogenic and/or embryocidal effects have been
demonstrated for ribavirin in all animal species studied.
"The current body of data on Pegasys monotherapy shows that it
may be a treatment option that provides better tolerability and
higher response rates for hepatitis C patients with and without
cirrhosis," said Dr. Chris Pappas, medical director at Hoffmann-La
Roche. "Recognizing that ribavirin is another antiviral proven
effective in combination with interferon, Roche is investigating
the combination of Pegasys with ribavirin."
About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver, is a
leading cause of cirrhosis and liver cancer and the number-one
reason for liver transplants in the U.S. An estimated four million
Americans are infected with the virus, with 35,000 to 180,000 new
infections each year. In the United States, the Centers for Disease
Control and Prevention estimate that hepatitis C is responsible for
eight to ten thousand deaths per year and could increase to 38,000
by the year 2010, surpassing annual HIV/AIDS deaths.
Hepatitis C is a blood-borne virus transmitted through body
fluids, primarily blood or blood products, and sharing needles. In
many patients, the mode of transmission is unknown. Unfortunately,
most people who are infected with hepatitis C are unaware of it
because, like HIV, it may take years for symptoms to develop. In
addition, it is estimated that as many as 40 percent of people with
HIV may be co-infected with hepatitis C.
SOURCE: Doctor's Guide to Medical News
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