Schering-Plough Corporation posted results from a planned interim analysis of an ongoing phase II study of boceprevir, its investigational oral hepatitis C protease inhibitor, in 595 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1. The ongoing study evaluates boceprevir in 28-week and 48-week treatment regimens.

In a 28-week treatment regimen in which patients received 4 weeks of Pegintron (peginterferon alfa-2b) and Rebetol (ribavirin, USP) prior to the addition of boceprevir (800 mg TID), the rate of sustained virological response at 12 weeks after the end of treatment (SVR 12) was 57 per cent (ITT).(1-3) Importantly, this treatment regimen provided an indication of early predictability of response, with patients who had undetectable virus (HCV-RNA) in plasma after 4 weeks of boceprevir treatment achieving an SVR 12 rate of 86 per cent.

"These interim results are very encouraging, especially given the response seen with a shorter course of therapy in a difficult-to-treat patient population," said principal investigator Paul Kwo, M.D., associate professor of medicine and medical director, liver transplantation, Department of Medicine, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, Indianapolis, who presented the data. "Boceprevir has been well tolerated by patients in this study, including in the longer duration treatment arms, and we look forward to further results from this ongoing study."

Overall, 77 per cent of the 595 patients in the study were enrolled in the United States. African-Americans represent 16 per cent of the patients enrolled and 7 per cent of patients in the study are cirrhotic.

In the ongoing study, known as HCV SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1), boceprevir (800 mg TID) is being evaluated in three treatment regimens: 4 weeks of Pegintron (1.5 mcg/kg once weekly) and Rebetol (800-1400 mg daily based on patient weight) therapy followed by the addition of boceprevir to the combination for 24 or 44 weeks (totaling 28 or 48 weeks of treatment); boceprevir in combination with Pegintron and Rebetol at the doses described above for 28 or 48 weeks (triple combination); and boceprevir in combination with Pegintron and low-dose Rebetol (400-1000 mg daily) for 48 weeks, compared to a control of Pegintron (1.5 mcg/kg once weekly) and Rebetol (800-1400 mg daily based on patient weight) alone for 48 weeks (an approved treatment regimen). The primary endpoint of the study is sustained virologic response after 24 weeks of follow up.

During a late-breaker oral presentation at EASL, Dr. Kwo presented interim results for the two 28-week boceprevir arms of the study. For patients receiving 4 weeks of Pegintron and Rebetol therapy prior to the addition of boceprevir, SVR 12 was 57 per cent (59/103), compared to 55 per cent (59/107) for patients in the boceprevir triple combination arm. For patients in these two boceprevir arms who had undetectable virus (HCV-RNA) after 4 weeks of boceprevir treatment (RVR), the SVR 12 rates were 86 per cent (53/62) and 74 per cent (31/42), respectively. SVR 12 rates are not yet available for patients in the 48-week boceprevir arms or the 48-week control arm, as treatment of these patients is ongoing.

Safety data from the study showed that the most common adverse events reported in the boceprevir arms were fatigue, anemia, nausea and headache. No increase in skin adverse events (rash or pruritus) beyond what was seen in the Pegintron and Rebetol control arm was observed. Treatment discontinuations due to adverse events were between 11 and 15 per cent for patients in the boceprevir arms, compared to 8 per cent for the control arm.

Early response rates at week 4 (RVR) and week 12 (EVR) of boceprevir treatment were increased for patients who received 4 weeks of Pegintron and Rebetol therapy prior to the administration of boceprevir (62 and 79 per cent, respectively), compared to patients in the triple combination (38 and 69 per cent) and control (8 and 34 per cent) arms, respectively. In the 28-week boceprevir arms, these patients also had a reduction in viral breakthrough compared to patients in the triple combination arm (4 vs. 7 per cent, respectively).

"The results seen with this novel treatment paradigm will influence the design of our future clinical studies, as we plan to consider RVR at week 4 of boceprevir treatment as the criterion for determining which patients can receive a shorter course of boceprevir therapy and which patients should continue treatment for 48 weeks," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "Additionally, this strategy has the potential to reduce the likelihood of the development of resistance by identifying patients who are responders to interferon and ribavirin prior to their receiving a protease inhibitor."

The rationale for this novel treatment regimen is based on the fact that both Pegintron and Rebetol reach steady-state concentrations by week 4, so patients have the protease inhibitor added at a time when the backbone drug levels have been optimized. In addition, the patient's immune system will have been activated and primed by Pegintron at the time that boceprevir is added to the regimen. This approach may minimise the period of time when there is a "functional monotherapy" with a direct antiviral, potentially reducing the likelihood for the development of resistance.

The HCV SPRINT-1 study is currently ongoing at sites across the United States, Canada and Europe. Final results from the study are anticipated to be available in early 2009, and will be submitted for presentation at an appropriate medical meeting.

In the United States, Pegintron is indicated for use alone or with ribavirin for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and who are at least 18 years of age.