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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