Schering’s Experimental Oral HCV Protease Inhibitor Boceprevir Appears Safe in Patients with Varying Degrees of Liver Impairment

By Ronald Baker, PhD

Boceprevir (SCH 503034) is an experimental oral HCV protease inhibitor that is under development by Schering-Plough for treatment of hepatitis C virus (HCV) infection. Preclinical studies have shown that the drug demonstrates potent antiviral activity in the HCV replicon system, and preliminary clinical trials in healthy volunteers and hepatitis C patients with compensated liver disease indicated that further study of boceprevir was warranted.

The primary objective of the current study, presented at the 42nd Annual Meeting of the European Association for the Study of the Liver this week in Barcelona, Spain, was to evaluate the pharmacokinetic parameters and safety profile of boceprevir in patients with stable chronic hepatic impairment. Results will help guide the development of dosing guidelines for patients with chronic liver disease.

This study was an open-label, single-dose, single-center study comparing boceprevir safety and pharmacokinetic parameters in patients with various degrees of hepatic impairment versus healthy subjects.

Hepatic impairment was evaluated according to Child-Pugh score. Mild hepatic impairment was defined as a score of 5-6, moderate impairment as a score of 7-9, and severe impairment as a score of 10-12.

Inclusion Criteria

Patients in the 3 groups with hepatic impairment had chronic liver disease for more than 1 year and were free of significant medical disorders unrelated to their hepatic disorder. Healthy subjects were free of clinically significant disease.

Exclusion Criteria

For patients with hepatic impairment:

• Clinically significant local or systemic infectious disease, except hepatitis C or hepatitis B, within 4 weeks before study drug administration;
• Lack of a stable medication regimen for at least 7 days before the study; Consumption of alcohol or caffeine within 48 hours before the study;
• Use of medications known to induce liver enzyme elevations within 72 hours before dosing;
• Primary biliary cirrhosis or any form of cholestatic disease;
• HIV antibody positive;
• Child-Pugh scores of 13-15;

For healthy subjects:

• Clinically significant local or systemic infectious disease, including hepatitis C or hepatitis B, within 4 weeks before drug administration;
• Use of any drugs except acetaminophen within 2 weeks and;
• Consumption of alcohol or caffeine within 48 hours before the study;
• Detectable HIV antibodies, hepatitis C antibodies, or hepatitis B surface antigen.

Study Design

Demographic characteristics of the study population are shown in Table 1.

Table 1

All subjects received a single dose of 400 mg boceprevir on Day 1 after a 6-hour fast. Blood samples were obtained immediately before dosing (time 0) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, and 72 hours after dosing.

Plasma samples were analyzed for boceprevir, and pharmacokinetic parameters were calculated, including maximum concentration (Cmax), time of maximum concentration (Tmax), area under the time-concentration curve (AUC), and half-life (t1/2).

Log-transformed data for AUC and Cmax were analyzed using an ANOVA model to extract the effects due to group according to liver disease status. Comparisons between groups with impaired hepatic status and healthy subjects were carried out using 90% confidence intervals for the mean differences.

Results

• Mean Cmax and AUC values for healthy subjects and patients with mild, moderate, and severe hepatic impairment increased with decreasing hepatic function.
  
  
• However, plots of individual Cmax and AUC values illustrate considerable overlap among the groups (Table 2).

• The ratio of the AUC in subjects with moderate hepatic impairment to the AUC in healthy subjects was less than 115 (15% increase relative to healthy subjects).
  
  
• The ratio of the AUC in severely impaired subjects to the AUC in healthy subjects was less than 150 (50% increase) (Table 2).
  
  
• The Cmax and AUC values for boceprevir in patients with severe hepatic impairment were within the exposure limits found to be safe, and represent values anticipated to produce a robust antiviral response.

Table 2

Safety

• 1 subject with severe hepatic impairment reported 1 adverse event, vomiting, that was mild in intensity and reversible.
• There    were no deaths or serious adverse events.
• No clinically significant changes in blood chemistry, hematological parameters, vital signs, or electrocardiograms occurred in any treatment group.
• 2 men in the group with severe hepatic impairment had prolonged QTcF intervals (>450 msec) that were present in both subjects at screening visits.
• No other subjects had a prolonged QTcF intervals at any time during the study. 

Conclusions

The researchers concluded that:

• A single 400 mg oral dose of boceprevir was well tolerated and safe in healthy subjects and patients with mild, moderate, and severe hepatic impairment.
• No boceprevir dose adjustment is required for patients with any degree of hepatic impairment receiving 400 mg of the drug.
• Further efficacy studies of boceprevir in HCV-infected patients with hepatic impairment are warranted.

 University of Miami, Division of Clinical Pharmacology, FL; Schering-Plough Research Institute, Kenilworth, NJ.

Commentary

Schering-Plough is undertaking a large clinical development program for boceprevir with the goal of developing new strategies for improving treatment outcomes for patients with chronic hepatitis C, including nonresponders to standard therapy and previously untreated (naive) patients. 

This is particularly critical for patients with difficult-to-treat forms of the disease that are resistant to current therapies. Specific subgroups of patients -- for example, African-Americans, patients with cirrhosis, patients coinfected with HIV, and liver transplant recipients -- are known to have different virological responses and safety profiles when treated for hepatitis C with current interferon-based regimens. 

Schering-Plough says the company is committed to evaluating boceprevir in these patient populations in future larger Phase III clinical studies or in separate trials focused on specific patient populations, as appropriate. 

In addition, Schering is collaborating with Wyeth/ViroPharma and Idenix/Novartis to conduct in vitro studies of boceprevir in combination with these companies’ experimental HCV polymerase inhibitors, HCV 796 and NM 107 (the active moiety of valopicitabine), respectively.

Phase 2 Studies

There were no data presented at the EASL meeting from Schering’s ongoing Phase II study of 800 mg thrice-daily boceprevir in combination with PegIntron and ribavirin in previous non-responders with genotype 1 HCV. However, the 350 or so patients in this study have completed treatment, and are all in the follow-up stage of the study. According to Schering-Plough, sustained virological response (SVR) data will be available later in 2007, and will help to guide the future clinical development of boceprevir.

Schering-Plough has also initiated the HCV SPRINT-1 study (HCV Serine PRotease INhibitor Therapy-1), a large Phase II study of 800 mg thrice-daily boceprevir in combination with PegIntron and ribavirin in treatment-naive genotype 1 patients. This trial is currently enrolling 400 participants in the U.S., Canada, and Europe. For complete information on the study, visit ClinicalTrials.gov: http://clinicaltrials.gov/ct/show/NCT00423670.

04/13/07

Reference  
R A Preston, A B Alonso, W Feely, and others. SCH 503034 (Boceprevir), an Oral HCV Protease Inhibitor, Is Well-Tolerated in Patients with Varying Degrees of Hepatic Impairment. 42nd Annual Meeting of the European Association for the Study of the Liver. April 11 - 15, 2007, Barcelona, Spain.

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