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Difference Between PEG ,
and PEGASYS?
(WebMD), 8/24/01 9:23 p.m.
The two pegylated versions of interferon alfa are not
identical by RockyRacoon (WebMD), 6/2/00 09:48:35 The two
pegylated versions of interferon alfa are not identical by
Harvey S. Bartnof, MD FDA approval for two pegylated versions
of interferon alfa * are expected this year. Pegasys (peginterferon
alfa-2a) from Hoffman-La Roche and Peg Intron (peginterferon
alfa-2b) from Schering are the two formulations that are under
FDA review. Widespread availability of these newer
formulations will have a great impact upon the treatment of
chronic hepatitis C. The differences and similarities of the
two formulations were discussed during a satellite meeting at
Digestive Disease Week 2000. The title was "Assessment of
Novel Hepatitis C Therapies: Pegylated Interferons and
Beyond." It was sponsored by Professional Postgraduate
Services and supported by an unrestricted educational grant
from Hoffman-La Roche. Teresa L. Wright, MD, from the Veterans
Administration Medical Center at the University of California
at San Francisco reviewed the "pharmacology" (study
of drugs) and "pharmacokinetics" (movement and
distribution of drugs) of pegylated interferon alfa. Variable
anti-Hepatitis C Virus effects Dr. Wright first addressed why pegylated
interferon alfa would be expected to have better anti-Hepatitis C Virus
(hepatitis C virus) effects than the non-pegylated versions.
When non-pegylated interferon alfa (NPIA) is injected at the
standard dose of 3 million international units (MIU) 3-times
weekly, the "trough" levels in-between doses are
quite low. During the last 12 hours of the 2-day dosing
interval, there is no detectable drug. This is due to the
short "half-life" (amount of time until half of an
original amount is remaining) of NPIA (3-5 hours) that leads
to inadequate antiviral activity in-between dosing, with Hepatitis C Virus
rebound that is observed with monotherapy. These factors
likely contribute to the "disappointing sustained
response rate" of NPIA monotherapy. It is also possible
that those fluctuations could contribute to certain of the
drug's side effects. Dr. Wright showed a graph depicting Hepatitis C Virus
viral load decreases during a 2-week period using different
"therapeutic" doses or regimens. When the standard
FDA dose of 3 MIU 3-times weekly of NPIA is given for two
weeks, the Hepatitis C Virus RNA initial decreases by approximately 1.5 log
(31-fold) during the first couple days and then returns
towards normal. Then there is a slow gradual decline to
slightly less than 1 log (10-fold) viral reduction from
baseline after two weeks. The second example was daily NPIA or
standard dose NPIA plus ribavirin. Each of those options leads
to an Hepatitis C Virus viral load reduction of approximately 3 log
(1,000-fold) reduction by two weeks. The third example was
pegylated interferon once weekly: this led to a viral load
reduction of approximately 3.5 log (3,100-fold) after two
weeks. Principles of "Pegylation" Then Dr. Wright
discussed the principals of "pegylation."
Polyethylene glycol (PEG) is a "non-toxic polymer"
(a substance with a high "molecular weight") that is
easily excreted in the urine, due to its being soluble in
water. The size of the pegylated polymer depends upon the
number of repeating units of carbon atoms attached to hydrogen
and oxygen. "PEG" also can be linear or branched. It
can be attached to the "base" substance (interferon
alfa, in this example) by different types of protein linkages.
These links or bonds may alter the stability of the
PEG-protein and may also affect its activity. The larger or
branched PEGs lead to a longer, sustained absorption period.
They also have a "reduced clearance" by the kidney.
(Clearance is measured as liters or volume per hour per
kilogram of body weight.) These larger/branched PEGs are
removed from the underlying interferon in the liver. Whereas,
smaller and linear PEGs will have a less sustained and shorter
absorption period. They have a "greater clearance"
by the kidney and are removed from the underlying interferon
in the kidney, not the liver. Dr. Wright said that there is a
"trade off between increased PEG size and reduced
specific activity." The point of significance will only
be determined by clinical studies of the two types. Overall,
PEG attachment to interferon alfa leads to a longer half-life
of the interferon. This occurs due to decreased
"clearance" by the kidney and reduced
"proteolysis" (slower breakdown of protein). In
addition, PEG attachment to interferon leads to lowered "antigenicity"
of interferon. This means less probability that the immune
system would make antibodies against interferon that can occur
among those who use NPIA. PEG attachment also leads to
increased chemical and thermal (heat) stability of the
"base" substance interferon. Differences between
Pegasys and Peg Intron Dr. Wright then reviewed some
differences between Pegasys and Peg Intron. Pegasys uses a
larger 40 "kilodalton" PEG that is attached to
interferon in a branched fashion. Whereas, Peg Intron uses a
smaller 12 "kilodalton" PEG that is attached to
interferon in a linear fashion. Each formulation has a PEG to
interferon ratio of one to one. Distribution of the two
formulations is somewhat different. Like NPIA, Peg Intron is
distributed widely throughout the body. Whereas, Pegasys is
distributed to the blood and organs, including the liver. This
means that there may be some compartments within the body that
Pegasys does not penetrate. Other differences include the
half-lives. Due to it's longer and branched-chain PEG, Pegasys
has a half-life ("terminal elimination") of 50-80
hours. Whereas, due to it's shorter and linear-chain PEG, Peg
Intron has a half-life of 30-50 hours. (Note that NPIA or non-pegylated
interferon alfa has a half-life of only 3-5 hours.) Later, Dr.
Wright characterized the half-lives of Pegasys and Peg Intron
as "similar." The "clearance" of the
formulations from the body is decreased when compared to NPIA.
Peg Intron has a 10-fold decreased clearance, while Pegasys
has a 100-fold decreased clearance. Each formulation will have
increased blood levels with multiple dosing. When using the
dose of 1 microgram per kilogram, Peg Intron had a maximal
blood serum (no cells) concentration approximately 24 hours
after a dose. With multiple weekly doses, the peak level of
Peg Intron was approximately 0.8 nanograms per milliliter,
with a gradual taper towards zero after the sixth day.
Whereas, Pegasys achieves maximal concentration 80 hours after
a dose, using its standard dose of 180 micrograms once weekly.
With multiple weekly doses, the peak level was approximately
25 nanograms per milliliter, which decreases to approximately
20 nanograms per milliliter at the end of the seventh day (the
end of the dosing interval). Dr. Wright said that Pegasys
definitely has some "protection from degradation"
and Peg Intron "likely" has the same. Doses used for
these calculations for Pegasys was 180 micrograms once weekly,
while that for Peg Intron ranged between 0.035 to 2 micrograms
per kilogram once weekly. Molecular differences were also
addressed by Dr. Wright. The amino acids involved in PEG
attachment to interferon in Peg Intron were lysine and
histidine. Whereas, the attachment in Pegasys is predominantly
lysine. The clinical relevance of that difference was not
discussed. A subtle difference in the attachment to interferon
of the linear versus branched PEG forms also was discussed.
Even though each form attaches in a "one to one
ratio" with interferon, more than one linear PEG
theoretically could attach to each interferon in Peg Intron.
"This "could in theory lead to aggregation or
blockage of the active site" [of interferon]. Whereas,
the single branched PEG in Pegasys "binds at a specific
site, [while the] active site likely remains unhindered."
It should be emphasized that these differences are
theoretical." Summing up the differences between Pegasys
and Peg Intron, Dr. Wright numerated the following factors.
"Clearance" of Pegasys is less than that of Peg
Intron. Pegasys "is metabolized by the liver;"
Peg Intron "is metabolized by the kidney." The
"area-under-the-curve" (total) concentration of
Pegasys is "more consistent" than Peg Intron. Dr.
Wright said that the "increase in levels [of drug] with
time may result in"……"either, both or
neither" of the following: increased efficacy or side
effects of [Pegasys] over [Peg Intron]. Similarities between
Pegasys and Peg Intron The similarities of Pegasys and Peg
Intron are as follows. Both can be administered once weekly
subcutaneously (under the skin). The half-life of each is
significantly longer than NPIA (non-pegylated interferon alfa).
Dr. Wright described the half-lives of each as being
"similar" to one another. Both have a favorable
"pharmacokinetic" or "PK" profile that
"supports improved efficacy over standard interferons."
In addition, multiple dosing of each leads to increased blood
serum levels. Final Thoughts Dr. Wright ended her talk by
reviewing that changing the "pharmacokinetics" of
interferon alfa with pegylation has resulted in once weekly
dosing and much reduced differences between peak and trough
(lowest) levels of active drug. The optimal dose of either
formulation will depend upon the results of clinical trials.
Reviewing the differences of Pegasys and Peg Intron, Dr.
Wright said that the significance of the various differences
between the two formulations would only be determined by
clinical studies. Studies to date clearly show that pegylated
interferon alfa monotherapy leads to greater levels of
sustained Hepatitis C Virus virologic responses. The sustained virologic
response rates will likely be even greater when combined with
ribavirin and/or other anti-Hepatitis C Virus agents. * Note that all four
generic versions use the spelling 'alfa' and not 'alpha'
interferon. 6/2/00 Reference: Wright TL. Pegylated interferons:
pharmacology and pharmacokinetics. Assessment of Novel
Hepatitis C Therapies: Pegylated Interferons and Beyond,
satellite symposium at Digestive Disease Week 2000; May 21-24,
2000; San Diego, California.
More here: Re: Difference
Between PEG , and PEGASYS?
by RockyRacoon (WebMD), 8/24/01 9:24 p.m.
Promising Results Reported from Trials of Two
"Peg" Interferons for Treatment of Hepatitis C Virus Roche's
Pegasys shows sustained response rate of 39% compared to 25%
for Schering's Peg Intron by Ronald Baker, PhD and Harvey S.
Bartnof, MD Hoffman-La Roche (Roche) and Schering Plough (in
partnership with Enzon Inc) are developing rival versions of
pegylated interferon for the treatment of chronic hepatitis C.
Roche's version of pegylated alfa interferon is called "Pegasys,"
(pegylated interferon alfa-2a) while Schering Plough's brand
is called "Peg Intron" (pegylated interferon
alfa-2b). Enzon and Roche have announced preliminary results
of Phase III trials of Peg Intron and Pegasys, respectively,
in the abstract book for the forthcoming 35th Annual Meeting
of the European Association for the Study of Liver Disease (EASL),
April 29-May 3, 2000 in Rotterdam, Holland. To view the
abstracts from the EASL meeting, CLICK HERE. Pegylated
interferon is created by attaching polyethylene glycol to alfa
interferon, allowing the drug to become more water-soluble and
to remain inside the body longer. This, in turn, enhances the
activity of the medication. The pegylated alfa interferons
require only once weekly subcutaneous dosing compared to three
times or more weekly dosing for the standard alfa interferons
(Intron A, Roferon, and Wellferon). Infergen, a
"consensus" interferon, is also used in the
treatment of chronic hepatitis C. The adverse side effects
from pegylated interferon are similar to those of standard
alfa interferon. These include "flu-like" symptoms
(fatigue, fever, headache), gastrointestinal symptoms,
depression, neutropenia,* and thrombocytopenia.** *
Neutropenia is an abnormal decrease in the number of
neutrophils (the most common type of white blood cells) in the
blood. ** Thrombocytopenia is a decreased number of blood
platelets (cells important for blood clotting). Phase III
Trial of Schering Plough's Peg Intron The phase III trial of
Peg Intron was a large, multi-center, double blind, controlled
study conducted in previously untreated patients with chronic
hepatitis C and compensated liver disease. The 1,219 study
participants were treated once weekly with one of three doses
of Peg Intron (0.5, 1.0 or 1.5 micrograms per kilogram) OR
three times weekly with 3 million International Units (MIU)
Intron A for 48 weeks. The trial was conducted for 72 weeks
that included 24 weeks of follow up. The primary efficacy
endpoint was sustained loss ("sustained virologic
response," SVR) of Hepatitis C Virus RNA 24 weeks following the end of
therapy. (Note weight in pounds times 0.454 = weight in
kilograms.) Study Population The study group was 63 percent
male and 91 percent Caucasian; 70 percent had Hepatitis C Virus genotype 1,
the most difficult Hepatitis C Virus genotype to treat successfully; 74
percent had Hepatitis C Virus RNA (viral load) greater than 2 million copies
per milliliter. The median baseline Hepatitis C Virus viral load was not
reported. Baseline liver biopsies revealed "Metavir"
fibrosis scores of 3 or 4 (4 is cirrhosis). Baseline liver
enzyme levels also were not reported. Study Results Patients
treated with all doses of Peg Intron experienced a
significantly greater loss of Hepatitis C Virus RNA during treatment
compared to those administered Intron A. Taking all study
participants into account, the sustained virologic response (SVR)
rates for those treated with 0.5, 1.0 or 1.5 micrograms per
kilogram of Peg Intron were 18%, 25% and 23%, respectively,
compared to a 12% SVR among those administered Intron A. Only
Hepatitis C Virus genotype non-1 and baseline Hepatitis C Virus RNA less than or equal to
2 million copies per milliliter were favorable indicators for
a SVR. Patients with these characteristics treated with 0.5,
1.0 or 1.5 micrograms per kilogram had a SVR of 53%, 59% and
69%, respectively. This compared to a 33% SVR among those
similar patients treated with Intron A. Liver biopsy results
at 72 weeks were not performed or not reported. Also, the
change in liver enzyme levels was not reported. The
investigators reported that adverse events were
"mild/moderate and manageable with dose adjustment."
Treatment discontinuation for adverse events was similar in
all treatment groups (6-11%). Dose reductions were similar for
Intron A and a Peg Intron dose of 0.5 and higher for Peg
Intron doses of 1.0 and 1.5 micrograms per kilogram. The
authors conclude that all three doses of Peg Intron were
"superior to and just as safe" as Intron A. They
anticipate that Peg Intron plus ribavirin will be more
effective than Intron A plus ribavirin, the current standard
of care. Full results of the phase III trial will be presented
on May 1 at the Rotterdam meeting. Phase III Trial of Roche's
Pegasys The Roche Phase III trial of Pegasys was a
multi-center, international study conducted in 531 treatment-naïïve
(no prior therapy) patients in Germany, Canada, the United
Kingdom, Spain, Taiwan, New Zealand, Switzerland, Mexico, and
Australia. Of the 531 study participants, 264 were randomized
to receive 12 weeks treatment with 6 million international
units (MIU) Roferon (interferon alfa-2a) subcutaneously three
times weekly, followed by 3 MIU Roferon three times weekly for
36 weeks. An additional 267 patients were randomized to
receive 180 micrograms Pegasys (pegylated interferon alfa-2a)
subcutaneously once weekly for 48 weeks. Study Population The
study group was predominantly male (67%) and Caucasian (85%),
with a mean age of 41 years. The percentage of patients with
Hepatitis C Virus genotype 1 (the most difficult genotype to treat) was 60%
in the Roferon group and 63% in the Pegasys group. The mean
Hepatitis C Virus viral load was 8.2 million and 7.4 million copies per
milliliter in the Roferon and Pegasys groups, respectively.
Patients with cirrhosis (liver scarring) or transition to
cirrhosis comprised 14 percent of those on Roferon and 12
percent of those on Pegasys. Baseline liver enzyme levels were
not reported. Study Results The 48-week virologic response
rates (less than 100 copies per milliliter using the Roche
Amplicor II Hepatitis C Virus RNA test) were 27 percent for the Roferon
group and 66 percent for those treated with Pegasys. The
sustained virologic response rates (SVR) at 72 weeks were 19%
of patients treated with Roferon and 39% of patients treated
with Pegasys. Liver biopsy results at 72 weeks were not
performed or not reported. Also, the change in liver enzyme
levels were not reported. The adverse side effect profile was
similar for both the Roferon and Pegasys groups. Dose
modification for neutropenia was required for seven percent
and 11 percent in the Roferon and Pegasys groups,
respectively. For thrombocytopenia, dose reduction was
required for 2 percent and 3 percent in the Roferon and
Pegasys groups, respectively. Discontinuation rates for drug
intolerance were 10% in the Roferon group and 7% in the
Pegasys group. The authors conclude that once weekly treatment
with Pegasys is significantly more effective than three times
weekly treatment with standard interferon (Roferon) and has an
"acceptable" safety profile. Commentary The major
limitation of these two phase III studies is that neither has
reported the change in liver biopsy results at 72 weeks. It is
likely that liver biopsies were performed and that the results
were not presented in their respective abstracts. Previous
studies have shown that, unlike HIV disease, Hepatitis C Virus RNA viral
load measurements do not correlate with liver biopsy findings.
Progression of liver disease is predicted by abnormalities
found on liver biopsy, not Hepatitis C Virus viral load. Another limitation
is that the type of statistical analysis was not reported for
either study. There is an assumption that an
"intent-to-treat" analysis was used (all patients
enrolled are included), but this was not specifically stated.
Sometimes, analyses are reported using an
"on-treatment" analysis, whereby patients who
discontinued are not included in the response percentages.
This would tend to overestimate the response rate. The Pegasys
study does indicate that all patients "treated" with
the respective drugs were included in their sustained response
rates. In addition, neither study reported baseline or
sustained liver enzyme levels. Previous studies have shown a
better outcome in patients with higher baseline liver enzyme
levels. A direct comparison of results from the phase III
trials of Peg Intron and Pegasys must be made with caution.
At first glance, Pegasys appears to be the superior
product, with a sustained response rate of 39 percent compared
to 23-25% for Peg Intron.
However, the mean baseline viral load levels in the Peg
Intron study were not presented, thereby precluding a direct
comparison. As stated above, baseline and sustained liver
enzyme levels were not reported; this also precludes a direct
comparison. Also, we do not yet know the sustained response
rates for each drug among patients with genotype 1. We do know
that the Peg Intron trial included more than twice as many
study participants and had a higher percentage of patients
with genotype 1 than the Pegasys trial: 1,219 versus 512, and
70 percent versus 63 percent, respectively. In addition, in
the Pegasys trial, the group treated with Roferon started
therapy with 6 MIU three times weekly for 12 weeks before
dose-reducing to 3 MIU three times weekly for the remaining 36
weeks. In contrast, in the Peg Intron trial, the Intron A
group was administered 3 MIU of that drug three times weekly
for the entire 48 weeks. These factors make a direct
comparison of the results of the two trials difficult. (The
SVR rate for Roferon was 19% compared to 12% for Intron A).
Enzon has maintained that it designed Peg Intron to have an
improved adverse side effect profile compared to standard
interferon (Intron A), but there are as yet no clear data to
support this assertion. More data from the two trials will be
released when the clinical investigators present their oral
reports at the EASL meeting in Rotterdam in early May. It
should be noted that both Pegasys and Peg Intron are
ultimately likely to prove most effective when used in
combination with ribavirin or Maxamine (histamine
dihydrochloride) or possibly both. At the very least, once
weekly subcutaneous injection with either of these new drugs
will provide patients with a welcome alternative to three or
more times weekly injections with standard alfa interferon.
The current standard of care of chronic hepatitis C is alfa
interferon administered three times weekly for 6-12 months
(depending upon genotype and viral load) in combination with
Rebetol (ribavirin). The FDA approved Schering Plough's
Rebetron (Intron A plus Rebetol) in the US in December 1998.
In clinical studies, alfa interferon plus ribavirin has
reduced Hepatitis C Virus viral loads below detectable levels in 31-36
percent of patients, when patients with all genotypes are
included. The effectiveness of standard alfa interferon, alone
or in combination with ribavirin, has been limited by serious
side effects in addition to the undesirable dosing schedule
(three or more times weekly), which has also adversely
affected patients' adherence. Development Status of Peg Intron
and Pegasys In February 2000 an advisory committee of the
European Agency for the Evaluation of Medicinal Products (EMEA)
recommended approval of Peg Intron for the treatment of
chronic hepatitis C in the European Union. Final marketing
approval by the EMEA is usually granted three months after the
Committee issues its approval advisory. Approval of this
application will allow Schering Plough to market Peg Intron
throughout the European Union. Also in February 2000, the FDA
accepted Schering Plough's December 23, 1999 filing for a
standard review (not expedited review) of Peg Intron powder
for injection for the treatment of chronic hepatitis C in
patients 18 years of age or older with compensated liver
disease. The FDA is required to act on this application for
approval within 12 months from the filing date (December 23,
1999). The company's filing proposes administration of Peg
Intron once weekly for one year. Schering Plough is also
developing Peg Intron as combination therapy with Rebetol (ribavirin)
for hepatitis C. The company initiated a multi-national phase
III clinical trial of the combination therapy in January 1999.
As outlined above, Roche has now completed a 72-week phase III
study of Pegasys that compares its safety and efficacy to
standard alfa interferon (Roferon). The company is expected to
file soon for approval of Pegasys. It is not known whether
Roche will ask FDA for expedited or standard approval for the
drug. Like Schering, Roche has initiated combination studies
of Pegasys with ribavirin. Expanded Access Program for Pegasys?
Roche has also submitted a request to FDA for initiation of a
large expanded access (EA) program for Pegasys, an action that
has won widespread support among Hepatitis C Virus and HIV treatment
advocates. EA programs traditionally have provided free access
to promising experimental drugs prior to their approval by
FDA. The Hepatitis C Action and Advocacy Coalition (HAAC) and
other Hepatitis C Virus and HIV community groups have lobbied Roche to ask
FDA for broad entry criteria to the Pegasys EA. It is hoped
the EA will allow access to the drug by a wide variety of
patients in need of effective Hepatitis C Virus treatment, including
patients co-infected with HIV and Hepatitis C Virus. FDA action on the Roche
expanded access program application is expected soon. 4/24/00
References: Trepo C and others. Pegylated interferon alfa-2b
(Peg Intron) monotherapy is superior to interferon alfa-2b (Intron
A) for the treatment of chronic hepatitis C. Abstract GS2/07.
35th Annual Meeting of the European Association for the Study
of Liver Disease (EASL). April 29-May 3, 2000, Rotterdam,
Holland. Zeuzem S and others. Evaluation of the safety and
efficacy of once-weekly peg/interferon alfa-2a (Pegasys) for
chronic hepatitis C. A multinational, randomized study.
Abstract GS2/08. 35th Annual Meeting of the European
Association for the Study of Liver Disease (EASL). April
29-May 3, 2000, Rotterdam, Holland. http://journals.munksgaard.dk/easl/html/home.htm
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