By Liz Highleyman

Given the suboptimal response and side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection, researchers are studying several small molecule agents that directly target various stages of the viral lifecycle (collectively known as "STAT-C").

One such drug is Schering-Plough's HCV NS3 protease inhibitor boceprevir (formerly SCH 503034). Data on boceprevir in combination with pegylated interferon plus ribavirin were presented this week at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco.

The HCV SPRINT-1 study is an open-label Phase 2 trial that enrolled 595 previously untreated patients with hard-to-treat HCV genotype 1. In Part 1, participants were randomly allocated to receive various schedules of 800 mg 3-times-daily boceprevir + 1.5 mcg/kg once-weekly pegylated interferon alfa-2b (PegIntron) + 800-1400 mg/day weight-adjusted ribavirin:

1. 4-week lead-in period of pegylated interferon + ribavirin, followed by addition of boceprevir for 24 weeks (total treatment duration of 28 weeks);

2. 4-week lead-in period of pegylated interferon + ribavirin, followed by addition of boceprevir for 44 weeks (total treatment duration of 48 weeks);

3. Boceprevir + pegylated interferon + ribavirin, all started at the same time and continued for 28 weeks;

4. Boceprevir + pegylated interferon + ribavirin, started at the same time and continued for 48 weeks;

5. Control arm: standard therapy with pegylated interferon + ribavirin for 48 weeks.

In a second part of the study that enrolled later, participants received boceprevir and pegylated interferon at the same dose for 48 weeks, but were randomly assigned to receive either 800-1400 mg/day ribavirin or a lower dose of 400-1000 mg/day (results not included in the present report).

The rationale behind the lead-in strategy is that both pegylated interferon and ribavirin reach steady-state concentrations by week 4, so patients in the lead-in arms delay starting boceprevir until the 2 "backbone" drugs have reached optimum levels. This may minimize the duration of "functional monotherapy" with boceprevir, thereby reducing the risk of resistance.

Most study participants (about 60% overall) were men, 77% enrolled in the U.S., 80% were white, 16% were black (a group that tends to respond poorly to interferon-based therapy), and the mean age was about 47 years. At baseline, about 7% had cirrhosis and about 90% had HCV RNA > 600,000 IU/mL.

The primary study endpoint was sustained virologic response (SVR), defined as continued undetectable HCV RNA 24 weeks after the completion of treatment using the Roche Cobas Taqman PCR assay with a limit of detection of 15 IU/mL.

Results

• In a planned interim analysis, addition of boceprevir in both the 28-week and 48-week regimens markedly increased the SVR rate compared with standard therapy.

• The SVR rate was higher with a 4-week pegylated interferon + ribavirin lead-in for the 48-week regimen:

• No lead-in, 28 weeks: 55%;
• Lead-in, 28 weeks: 56%;
• No lead-in, 48 weeks: 66%;
• Lead-in, 48 weeks: 74%;
• Standard therapy: 38%.

• Rapid virologic response (RVR) at week 4 and early virologic response (EVR) at week 12 were highly predictive of sustained response with the boceprevir combinations, as is the case for standard pegylated interferon/ribavirin therapy.

• RVR was a better predictor of SVR in the lead-in arms compared with the arms that started all drugs at the same time.

• Percentages of patients achieving SVR according to early response status were as follows:

• No lead-in, 28 weeks: RVR 74%; EVR 69%;
• Lead-in, 28 weeks: RVR 82%; EVR 68%;
• No lead-in, 48 weeks: RVR 82%; EVR 83%;
• Lead-in, 48 weeks: RVR 92%; 89%;
• Standard therapy: RVR 100%; EVR 86%.

• The rate of viral breakthrough decreased with both the 28-week and 48-week lead-in boceprevir regimens:

• No lead-in, 28 weeks: 7%;
• Lead-in, 28 weeks: 4%;
• No lead-in, 48 weeks: 11%;
• Lead-in, 48 weeks: 5%;
• Standard therapy: 0%.

• The most common adverse events (AEs) reported in the boceprevir arms were fatigue, anemia, nausea, and headache.

• AEs occurred at similar rates in the boceprevir and standard therapy arms with the exception of anemia, which was more common with boceprevir.

• Incidence of rash and pruritis (itching) were similar with the boceprevir regimens and standard therapy.

• The rate of treatment discontinuation due to AEs ranged from 9% to 19% for patients in the boceprevir arms, compared with 8% in the standard therapy arm.

"In this study, boceprevir when combined with [pegylated interferon/ribavirin] is safe for use up to 48 weeks," the investigators concluded. "Boceprevir substantially improves SVR rates with 28 weeks of therapy and nearly doubles the SVR compared to the current [pegylated interferon/ribavirin] standard of care for 48 weeks."

Further, they added, "Use of a 4-week lead-in with [pegylated interferon/ribavirin] prior to the addition of boceprevir appears to reduce the incidence of viral breakthrough regardless of treatment duration and may improve SVR over a 48-week treatment duration."

"The high response rates seen with boceprevir in this study are very exciting, especially given that genotype 1 is the most common and hardest to treat form of hepatitis C," said lead investigator Paul Kwo, MD, of Indiana University School of Medicine in a press release issued by Schering-Plough. "Boceprevir was well tolerated by patients in this study, and the use of the 4-week lead-in prior to the addition of boceprevir appears to reduce the incidence of viral breakthrough regardless of treatment duration and may improve SVR over a 48-week treatment period."

Schering-Plough is currently conducting 2 large ongoing pivotal Phase 3 studies of boceprevir plus PegIntron and ribavirin in patients with chronic genotype 1 hepatitis C, one for treatment-naive individuals (HCV SPRINT-2) and the other for patients who failed prior treatment, both relapsers and non-responders (HCV RESPOND-2). Together, these studies are expected to enroll more than 1400 participants in the U.S. and at international sites. For more information about these studies, visit www.clinicaltrials.gov and search for "boceprevir."

Indiana University Medical Center, Indianapolis, IN; Alamo Medical Research, San Antonio, TX; Mount Vernon Endoscopy Center, Alexandria , VA; University of Miami Center for Liver Diseases, Miami, FL; Baylor College of Medicine, Houston, TX; Indianapolis Gastroenterology Research Foundation, Indianapolis , IN; South Florida Center of Gastroenterology, Wellington, FL; Liver Specialists of Texas, Houston, TX; Henry Ford Hospital, Detroit, MI; Digestive Disease Associates, Baltimore, MD; University of California-Davis, Sacramento, CA; Liver and Intestinal Research Center, Vancouver, BC, Canada; Weill-Cornell Medical College, New York, NY; Digestive Healthcare of Georgia, Atlanta, GA; Schering-Plough Research Institute, Kenilworth, NJ.

11/04/08

Reference
P Kwo, E J. Lawitz, J McCone, and others. HCV SPRINT-1: Boceprevir plus Peginterferon alfa-2b/Ribavirin for Treatment of Genotype 1 Chronic Hepatitis C in Previously Untreated Patients. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract LB16.

Other source
Schering-Plough Corp. Boceprevir Phase Ii Study Showed High Rate Of Sustained Response With 28- And 48-Week Regimens In Genotype 1 Treatment-Naive Hepatitis C Patients. Press release. November 1, 2008.