Top-line results of the first large-scale comparison of the two leading combination treatments for hepatitis C virus (HCV) were released on January 14th by drug company Schering-Plough. In previously untreated patients with HCV genotype 1, similar rates of sustained virologic response (SVR) were reported after up to 48 weeks of combination therapy with either Schering's PegIntron (peginterferon alfa-2b) and Rebetol (ribavirin), or with Roche's Pegasys (peginterferon alfa-2a) and Copegus (ribavirin).
An experimental lower dose of PegIntron resulted in similar response rates; fewer instances of virologic relapse were seen in patients at either dose of Pegintron versus those receiving Pegasys.
Data quoted in this report are taken from Schering's news release of the study results. Complete results of the IDEAL study are forthcoming.
Dosing, study design, and study population
The current standard treatment for chronic HCV infection is combination therapy with pegylated interferon plus ribavirin. Currently, two major pharmaceutical companies manufacture formulations of both drugs: Schering-Plough markets peginterferon alfa-2b as Pegintron and ribavirin as Rebetol; Roche produces peginterferon alfa-2a as Pegasys and ribavirin as Copegus.
The IDEAL study (Individualized Dosing Efficacy vs. flat dosing to Assess optimal pegylated interferon therapy) was a randomised Phase IIIb clinical trial undertaken by Schering-Plough, which compared treatment with Pegasys and Copegus to treatment with Rebetol plus a standard or a lowered dose of Pegintron. Co-principal investigators were renowned hepatitis C researchers John McHutchison and Mark Sulkowski.
As per the approved US product label, the standard dose of Pegasys is 180 mcg/week regardless of body weight. Copegus is dosed at 1000mg/day for patients weighing less than 75kg, or 1200mg/day for those ≥ 75 kg (when treating HCV genotype 1). The standard dose of Pegintron is 1.5mcg/kg/week. The standard daily dose of Rebetol is 800mg, although studies have suggested that increased doses may be more effective.
The IDEAL study population consisted of 3070 previously untreated US patients with HCV genotype 1, the most common form of the virus worldwide and the one least likely to respond to treatment. Of these participants, 82% had an HCV viral load ≥ 600,000iu/ml, 11% had grade F3/4 liver fibrosis or cirrhosis, and 19% were African Americans. HIV co-infection status was not reported. The study was conducted at 118 academic and community centres across the United States.
Participants were randomised to one of three treatment regimens (no significant differences in patient characteristics were reported across the three treatment arms):
(1) PegIntron 1.5mcg/kg/week (the standard dose) plus Rebetol, 800 to 1400mg/day (an investigational dose, adjusted by four weight categories).
(2) PegIntron 1.0mcg/kg/week (an investigational lower dose) plus Rebetol, 800 to 1,400mg/day (as in arm 1).
(3) Pegasys 180mcg/week plus Copegus, 1,000 to 1,200mg/day according to weight (standard doses for both drugs).
As a result, 1598 of the 3070 participants (52%) were assigned the same dose of ribavirin (either Rebetol or Copegus) based on their weight groups.
Dosing of PegIntron and Pegasys was unblinded, so both physicians and patients knew which product they were receiving.
Participants received up to 48 weeks of combination therapy with 24 weeks of follow-up; further details on treatment duration were not provided.
Results
Sustained virologic response (SVR) at the end of treatment, the primary endpoint of the study, was defined as undetectable HCV RNA at 24 weeks after the end of treatment (as measured by Roche's Cobas Taqman 1.0 assay, with a lower limit of detection of 15iu/ml). Twelve-week post-treatment data were used if 24-week post-treatment data were not available.
SVR was reported as similar for the three treatment regimens: 40% for the 1.5mcg PegIntron arm, 38% for the 1.0mcg PegIntron arm, and 41% for the Pegasys arm. Patients receiving PegIntron were reported as being less likely to show virologic relapse after the end of treatment, compared to Pegasys (24% vs. 20% vs. 32%, respectively). Further statistical details (p-values and confidence intervals) and the time to relapse were not available from the news release.
SVR also was similar among those who were assigned equivalent doses of ribavirin based on their weight group (40% vs. 38% vs. 38%, respectively). Relapse rates after discontinuation were also lower in both PegIntron/Rebetol arms for those participants who received equivalent ribavirin doses (22% vs. 20% vs. 35%, respectively).
Overall adverse events were reportedly similar between the three treatment regimens, as were discontinuation rates due to adverse events (13% vs. 10% vs. 13%, respectively). "Flu-like symptoms" were the most commonly reported adverse events in all three study arms.
Robert J. Spiegel MD, chief medical officer and senior vice president, Schering-Plough Research Institute, stated that "with these results, we now have, for the first time, a large body of well-controlled clinical data demonstrating how the similarities and differences of the two leading combination therapies for hepatitis C affect outcomes for patients. We look forward to further analyses of this large data set to gain additional clinical insights into the management of this serious disease."