Hepatitis C - R-7128

Hepatitis C causes liver inflammation; however, frequently patients remain asymptomatic for many years before it causes them problems. Ultimately, it can result in serious health issues such as fibrosis, cirrhosis, liver cancer and liver failure. Even when the infection is identified early, the standard treatment of an interferon-alpha and the antiviral prodrug ribavirin is unpleasant and far from guaranteed to succeed.

Up to half of all patients with HCV-1 do not respond to this treatment, and alternative therapies are much needed. One potential target is the NS5B protein on the virus, which is an RNA-dependent RNA polymerase that is essential in the viral replication process. Several drugs that act by this mechanism have reached the clinic, but have largely failed.

Another such molecule, R-1656, was developed by Roche and Pharmesset, and while it worked in the lab and results of a Phase I trial were positive, pharmacokinetic studies in rhesus monkeys showed its oral bioavailability was poor, and its absorption was both too slow and incomplete. Hence the prodrug R-7128 was developed, and it is now in trials in combination with pegylated interferon and ribavirin in treatment naïve patients.

In one trial, 40 patients who had failed interferon therapy were given the drug in doses of 750 or 1,500mg once a day, the same doses twice a day or placebo for 14 days.¹ Decreases in HCV RNA were dose dependent. Side-effects were common in patients given placebo, and included headache, diarrhoea, nausea, fatigue and dry mouth. The maximum tolerated dose was not reached, and no signs of the development of resistance were observed.

It has also been investigated in patients with HCV-2 and HCV-3.² A total of 10 patients with HCV-2 and 15 with HCV-3 who had previously failed interferon therapy were given 1,500mg of the drug twice a day in combination with standard therapy, and five were given placebo plus standard therapy. Response rates were 90% in the HCV-2 group, and 60% in those with HCV-3.

A double blind, placebo-controlled trial was also carried out in 50 treatment naïve patients with HCV-1 in combination with peginterferon alpha-2a and ribavirin.³ Subjects were given 500mg or 1,500mg of the drug or placebo twice a day on top of standard therapy. After four weeks, 85% of those given the higher dose had a rapid virological response, compared with 30% of the lower dose group, and just 10% of those given placebo. With the higher dose, the rate increased from 10% in the first week, and there was no difference in response between different racial groups, which is commonly observed with standard treatment.