Roche has moved quickly to downplay the significance of top-line results from the first large randomised clinical trial directly comparing the two leading therapies for chronic hepatitis C, Schering-Plough’s Pegintron (peginterferon alfa-2a) and Roche’s own Pegasys (peginterferon alfa-2a).

The data reported by Schering-Plough showed that the three combination regimens assessed in the IDEAL (Individualised Dosing Efficacy vs Flat Dosing to Assess optimaL pegylated interferon therapy) trial were similarly effective at treating hepatitis C, although fewer patients who received one of two Pegintron regimens relapsed following the end of treatment than those given Pegasys.

Roche, which scuppered Schering-Plough’s dominance of the hepatitis C market after it launched Pegasys in 2002, claims there were “clear biases” towards Pegintron in the design of the IDEAL study, due to varying doses of the antiviral ribavirin administered in combination with the rival drugs. Schering-Plough insists the combination regimen of Pegasys and Copegus (ribarivin) used “the recommended doses in accordance with their approved US labelling”.

The IDEAL trial’s comparison of the approved dose of Pegintron (1.5 mcg/kg/week) plus ribavirin (Rebetol, 800-1,400mg/day) and a lower dose of Pegintron (1.0 mcg/kg/week) plus the same dose of Rebetol was a post-approval commitment to the US Food and Drug Administration. Schering-Plough said it had added the comparison with Pegasys/ribavirin as “no randomised, controlled head-to-head study of the two available peginterferon regimens had been conducted to date”, while cross-study comparisons and retrospective analyses of previous data were “difficult to interpret because of differences in study designs, patient populations and assay limits”.

The full results of the IDEAL study will be submitted for peer-reviewed publication and presentation at forthcoming medical meetings, as well as to health authorities worldwide, the US company noted. The trial involved 3,070 previously untreated US patients with hepatitis C virus (HCV) genotype 1, the most common form of the virus worldwide and the most difficult to treat. They were randomised to one of three treatment regimens – the two doses of Pegintron plus Rebetol already mentioned, or Pegasys 180 mcg/week plus Copegus 1,000-1,200 mg/day.

The Copegus dose was adjusted for two and the Rebetol dose for four weight categories. As a result, 52% of patients were assigned the same dose of ribavirin (either Copegus or Rebetol) based on their weight group. Otherwise, 39% of patients in the Pegasys arm were given a higher dose of ribavirin while 9% of patients in the Pegintron arm received a higher dose, Schering-Plough said. Combination therapy in both arms was continued for up to 48 weeks, with 24 weeks of follow-up. The primary endpoint for the IDEAL trial was sustained virologic response (SVR) to hepatitis C therapy.

SVR scores
The top-line data revealed that SVR overall was 40% for Pegintron 1.5 mcg/kg/week plus Rebetol, 38% for Pegintron 1.0 mcg/kg/week plus Rebetol, and 41% for Pegasys 180 mcg/week plus Copegus, Schering-Plough reported. Once treatment was over, though, 24% and 20% respectively of patients on the higher- and lower-dose Pegintron combination regimens relapsed, compared with 32% of patients taking the Pegasys regimen.

Results were similar (although Pegasys came off worse) among those patients who were assigned equivalent doses of ribavirin (Copegus or Rebetol) based on their weight group – i.e., SVR was 40% for Pegintron 1.5 mcg/kg/week plus Rebetol, 38% for Pegintron 1.0 mcg/kg/week plus Rebetol and 38% for Pegasys 180 mcg/week plus Copegus, while relapses were 22%, 20% and 35% respectively.

Adverse events were similar for all three treatment regimens – including the lower dose of Pegintron – and were comparable to those seen in other studies, with a range of ‘flu-like symptoms’ the most commonly reported. Discontinuation rates for the higher- and lower-dose Pegintron regimes were 13% and 10% respectively; the rate was 13% for the Pegasys/Copegus combination.

“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,” commented Dr Robert Spiegel, chief medical officer and senior vice president, Schering-Plough Research Institute. “These findings provide important clinical-based evidence that will help physicians in making treatment decisions and in guiding their patients through what is a long and challenging course of therapy.”

Dosing mismatch
Roche begged to differ, arguing that the mismatch in ribavirin dosing schedules between the Pegintron and Pegasys arms of IDEAL “introduces several potential biases into the study because experts agree that an optimised dose of ribavirin, with either pegylated interferon, is critical to achieving success in hepatitis C treatment. In particular, maintaining a full dose of ribavirin has shown an important ability to reduce relapse following the end of treatment.”

Not only did the starting doses of ribavirin differ in the Pegintron and Pegasys arms, but the IDEAL study design called for a more drastic ribavirin dose reduction for side-effect management in most patients in the Pegasys arm compared with those in the Pegintron arms, Roche said. In some cases, it added, ribavirin dose reductions in the Pegasys arm were three times greater than in the Pegintron arms. As a substantial number of hepatitis C patients need to have their ribavirin dose reduced to manage side-effects, these adjustments could have an impact on efficacy, Roche suggested.

It also complained that the Pegasys arm of the trial was not blinded; and that erythropoietin (EPO) – often given to treat ribavirin-related anaemia and to help patients maintain a higher ribavirin dose – could only be prescribed after the first-dose ribavirin reduction. “Since patients in the Pegintron arms generally had smaller ribavirin dose reductions, this introduces another potential bias and means those Pegintron patients were potentially able to maintain a higher dose of ribavirin compared to Pegasys patients,” the company stated.

It quoted Dr Douglas Dieterich, professor of medicine in the Division of Hepatology at Mt. Sinai School of Medicine in New York City, as saying: “I do not expect that the results of the IDEAL study will meaningfully impact clinical practice, except to inform physicians on the appropriate dosing of Pegintron and to reinforce the already widely-accepted view that optimising ribavirin dosing throughout treatment is critical to achieving success and preventing treatment relapse in hepatitis C.”