Debiopharm develops Hepatitis C Debio-025

4-May-2011

Targets cyclophilins, which are intracellular binding proteins expressed in many tissue types

The viral infection hepatitis C affects the liver, and while it can cause severe problems, including fibrosis, cirrhosis, liver cancer and liver failure, often those who have contracted the virus have no idea they have been infected until symptoms appear many years later. The most common treatment regimen involves a combination of a pegylated interferon and the antiviral drug ribavirin, but this is frequently ineffective. Thus new treatments are much needed.

A new treatment, Debio-025, is being developed by Swiss company Debiopharm. It targets cyclophilins, which are intracellular binding proteins that are expressed in many different types of tissue, and are involved in numerous processes within the cells such as immune response and mitochondrial function. Cyclophilins are also vital in hepatitis C replication, and blocking cyclophilin in vitro can reduce this replication. Debio-025 is a modified form of the immunosuppressant ciclosporin, which does not have its immunosuppressive effects but does have a good antiviral activity against both HCV and HIV in vitro.1 Several clinical trials have already been carried out.

In the first of these, treatment naïve patients infected with HCV, who may or may not also have had HIV infection, were given 1200mg of the drug or placebo twice a day for 14 days in a randomised, double blind, placebo-controlled trial.2 The mean HCV viral load was significantly decreased in all those given the active, and in all the three different genotypes of virus with which the patients were infected 1, 3 and 4. The absence of viral rebound during treatment implied that the drug has a high barrier for the selection of resistance. The drug was generally well tolerated, although about half of the 19 given the active developed hyperbilirubinaemia, and four of these discontinued treatment as a result. This returned to normal after treatment ended.

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It has also been investigated in combination with pegylated interferon alfa 2a. The multicentre, randomised, double blind, placebo-controlled escalating dose ranging Phase II study was again carried out in treatment naïve hepatitis C patients.3 Subjects were given daily doses of 200, 600 or 1000mg of the drug plus 180µg of the interferon a week for four weeks. This regimen was compared with monotherapy with either the interferon alone or the highest dose of Debio-025 alone. The two higher dose combination treatments caused a continuous decay in viral load. Adverse events were similar between the different treatment groups, with the exception of reversible hyperbilirubinaemia again at the highest dose of Debio-025, and a higher incidence of neutropoenia among those given the interferon. Trials continue, including in patients who did not respond to standard therapy.

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