Preliminary Results of Pegasys (pegylated interferon) plus Ribavirin Study for Chronic Hepatitis C

• "End-of-Treatment" rates only were presented.
• Full analysis of "Sustained Virologic Response" rate is underway.

While EASL 2001 formally begins tomorrow, pre-Conference Satellite sessions have taken place for 3 days. Roche Pharmaceuticals had their Satellite Symposium today. Preliminary results of their large, phase III study evaluating the benefits of Pegasys (pegylated interferon alfa) plus ribavirin were presented. However, the full and complete results, including the important "sustained virologic response" rates will not be presented until DDW (Digestive Disease Week), which will take place next month in Atlanta, Georgia. The interim results were presented by Adrian M. Di Bisceglie, MD of St. Louis University in Washington. Pegasys is under development by Roche.

A total of 1,143 treatment-naïve (no previous therapy) patients with chronic hepatitis C were randomized into 1 of 3 treatment arms. They were: (1) standard Rebetron which consists of interferon alfa-2b (Intron A) 3 MIU (million international units) injected 3-times weekly plus oral ribavirin 1,000-1,200 mg once daily; (2) pegylated interferon alfa-2a (Pegasys) 180 micrograms injected once weekly plus oral placebo; and (3) pegylated interferon alfa-2a 180 micrograms injected once weekly plus oral ribavirin 1,000-1,200 mg once daily. Randomization was to one of 3 treatment arms in a ratio of 2: 1: 2 for arms (1), (2), and (3), respectively. Treatments were for 12 months. All patients had a positive test for HCV RNA, an increased ALT (alanine amino transferase, liver enzyme) and a presumed abnormal liver biopsy.

Some baseline specifics about the patients were presented and indicated that the 3 arms were well balanced in terms of HCV genotype 1 (the most difficult to treat), HCV RNA concentration and percentage with cirrhosis (scarring, fibrosis score F4) on liver biopsy. The percentage of each arm with HCV genotype 1 was 64% (arm 1), 66% (arm 2) and 64% (arm 3). The mean baseline HCV RNA was 5.8 million copies per milliliter (arm 1), 5.9 million copies/mL (arm 2) and 5.9 million copies/mL (arm 3). The percentage with cirrhosis was 15% (arm 1), 12% (arm 2) and 12% (arm 3). The following baseline information was not presented: mean age, gender percentages, race-ethnicities, mean liver enzyme levels, body weight, tolerability, and duration of HCV infection. All patients were HIV negative.

The interim results were as follows. Using a strict "intent-to-treat" analysis (all enrolled patients included whether or not they received study drug), at the end of 48 weeks of treatment (end of treatment response or ETR), the percentages with an undetectable HCV RNA for each arm were: 51% (arm 1), 58% (arm 2), and 68% (arm 3).

The sustained virologic response (SVR) rates, the standard measurement of efficacy 6 months after treatment is finished, were not presented. However, it is always the case that SVR rates are less than ETR rates. The following also were not presented: changes in liver enzymes, liver biopsy changes, adverse events, dose modifications, and discontinuation rates. These data also do not report differences in responses between genotypes.

Reported at last year’s EASL were these two pegylated interferon monotherapy studies.

Editorial note: So, the ETR for Pegasys monotherapy in the study reported at this year’s EASL meeting was less than reported in last year’s EASL (69% vs 58%), but greater than that reported for Peg Intron monotherapy (58% vs 49%).

A large, phase III study of 1,530 patients showed that for those patients who were randomized to peginterferon alfa 2b (PegIntron) at a dose of 1.5 mg per kilogram injected once weekly with daily oral ribavirin of 800 mg they had an SVR of 54% (62% <65kg, 55% 65-85kg, 49%>85kg). For those with genotype 1, the SVR was 42%; for those with genotypes 2 or 3, the SVR was 82%.

Editorial note: When they used optimized weight dosing (retrospective analysis based on weight of patient) the overall SVR improved to 61%. However, the SVR for individuals received standard IFN+RBV was higher than usual 47% vs 40%. Study investigators said this was due to improved patient management reflected in less discontinuations and more dose modifications. 42% of study participants had dose reductions in the Peg-Intron+RBV study vs 10% in the large international study of IFN 3 MIU 3-times per week + ribivarin. There was a difference in discontinuations as well—14% in the Peg+RBV study vs 19% in the international standard IFN+RBV study.

Recall that even without a SVR, there is evidence that liver histology improvements still may occur. And liver biopsy is what ultimately is associated with liver disease and potential death.

While it may be easy to speculate what the SVR rates will be for the newest study first presented above, it would be just that: mere speculation. The SVR rates will be presented in approximately one month. And then, some comparison could be made between Pegasys plus ribavirin versus PegIntron plus ribavirin, even though the study does not directly compare each dual therapy. However, a large study with true "head-to-head" comparison of the two double therapies is unlikely to take place.