Boceprevir – Experimental Drug for Chronic Hepatitis C Infection

Under development by Schering-Plough, boceprevir is an oral HCV protease inhibitor indicated for the treatment of chronic infection with hepatitis C (HCV). It is currently in Phase III development.

Few treatment options for HCV infection

HCV is an infection of the liver caused by the hepatitis C virus. It is most commonly transmitted by blood-to-blood contact. Before routine screening for HCV, people were at risk of contracting HCV infection through the use of contaminated blood products in blood transfusions (post-transfusion hepatitis). It is common in HIV positive patients: about a third of all HIV patients are co-infected with HCV.

While some people infected with HCV spontaneously clear the infection, for the majority of patients HCV is a chronic disease. Current treatment options for patients with chronic HCV are limited. At present, standard treatment of HCV infection usually consists of oral ribavirin, a nucleoside analogue, in combination with a pegylated interferon, which is administered by injection.

The aim is to achieve a sustained virological response (SVR), in which HCV is no longer detectable in the blood for six months after the cessation of treatment. Most patients undergo treatment for an initial 12 weeks, with responders often continuing for periods of up to 48 weeks. Patients with HIV/HCV co-infections may require even longer periods of treatment.

Because many patients with chronic HCV infection fail to respond to current therapy, or respond only poorly, there is a need for new and improved drugs to treat this serious and potentially fatal liver disease.

Direct antiviral therapy for HCV

Currently approved treatments for chronic HCV infection are designed to boost the host's immune response to help eradicate the virus. In contrast, Schering-Plough's boceprevir is designed to directly attack the virus by inhibiting protease enzymes that are critical to HCV replication. Clinical studies suggest that it is a potent addition to standard therapies in patients with HCV genotype-1, the most common and hardest form of HCV to treat.

In HCV SPRINT-1, a Phase II study in 595 treatment-naïve patients with chronic HCV genotype 1, treatment with boceprevir improved viral clearance rates in comparison with standard therapy alone. In this 48-week study, SVR rate at 12 weeks after the end of treatment was 74% in patients who received four weeks of peginterferon alfa-2b and ribavirin before the addition of boceprevir 800mg tid (standard therapy lead-in), compared to 38% for patients receiving 48 weeks of standard therapy alone.

SVR at 12 weeks was 66% in patients who received 48 weeks of boceprevir in combination with peginterferon alfa-2b and ribavirin from the beginning of treatment (standard therapy lead-in). For patients who received the standard therapy lead-in and experienced a rapid virological response (undetectable HCV-RNA in plasma after four weeks of boceprevir treatment), SVR was 82% in the 28-week regimen and 92% in the 48-week regimen.

Boceprevir has also demonstrated efficacy in HCV patients who failed to respond to prior treatment with peginterferon alfa-2b/ribavirin combination therapy. These so-called "null nonresponders" constitute the most difficult to treat HCV patient population.

Boceprevir advances to Phase III development

On the back of successful Phase II studies, boceprevir progressed to Phase III development where it is being studied in combination with peginterferon alpha-2b and ribavirin.

One trial was to focus on treatment-naïve patients (HCV SPRINT-2), while the second was to enrol patients who have failed previous treatments including both relapsers and non-responders (HCV RESPOND-2). The two tests are randomised, double-blind, placebo-controlled trials running concurrently.

Schering completed enrolment of patients for SPRINT-2 in January 2009. Patient enrolment for RESPOND-2 was completed in November 2008. About 1,500 patients have been enrolled in centres across the US and other international sites. The trials are expected to be completed by mid-2010.

Marketing commentary

Estimates from the WHO suggest that as much as 3% of the world's population has HCV, 80% of whom are chronically infected. It is a major cause of liver cirrhosis and liver cancer.

Current drug therapy offers benefit to some patients with chronic HCV infection: about 30–50% of patients respond to combination peginterferon alpha-2b/ribavirin therapy. Nonetheless, a large treatment gap remains for which HCV protease inhibitors represent a potentially important new class of drugs.