Some Emerging HCV Therapies

By Sean R. Hosein
From Canadian AIDS Treatment Information Exchange

December 23, 2010

Underlying some of the research with new anti-HCV agents is the hope that peginterferon, and eventually ribavirin, can eventually be replaced with more tolerable agents. This may not be possible in the immediate future, but some researchers hope that over the next five years perhaps less time spent taking peginterferon and ribavirin may be a possibility for future HCV treatment regimens.

Anti-HCV drugs under development can be divided into several groups, or classes, depending on how they work.

Protease Inhibitors

HCV needs enzymes called NS3/4A proteases that help HCV-infected cells produce new copies of HCV. These enzymes also appear to suppress the ability of infected cells to alert other cells about attack by HCV. So HCV protease inhibitors could have several benefits.

Drug companies often seek to get their drugs first approved by regulatory authorities in the United States, followed by the European Union and then Canada, Australia, Japan and other high-income countries. This is because the U.S. and the EU have large, relatively wealthy populations and present opportunities for sales and profit for drug companies. Also, it is likely that new therapies for HCV will first be approved for use in HCV mono-infection because there are more cases of mono-infection than co-infection and new therapies were initially developed for treating HCV mono-infection.

The two new anti-HCV drugs that are most likely to be approved in the U.S. are the protease inhibitors telaprevir (made by Vertex Pharmaceuticals) and boceprevir (made by Merck).

Both of these drugs have shown powerful anti-HCV activity in clinical trials of HCV mono-infection when taken as part of regimens that contain peginterferon and ribavirin. These protease inhibitors are also useful in people who have previously been treated with standard HCV therapy (peginterferon and ribavirin) but who did not respond.

Boceprevir and telaprevir are expected to be approved in the United States in 2011, with approval in the EU probably occurring in the same year. These drugs are expected to be approved in Canada in 2012.

Both of these protease inhibitors must be taken three times daily and can have side effects such as anemia. Therefore, interest in other HCV protease inhibitors under development -- such as TMC 435350 (made by Tibotec) and GS 9256 (made by Gilead Sciences) -- as well as other drugs by other companies is intense.

Polymerase Inhibitors

These drugs represent another class of anti-HCV agents and interfere with an enzyme called polymerase (hence their name). Examples of polymerase inhibitors include RG7128 and RG1628 (being developed by Hoffmann-La Roche), ABT 072 and ABT 333 (being developed by Abbott) and GS 9190 (being developed by Gilead Sciences).

Cyclophillin Inhibitors

Cyclophillins are receptors for the compound cyclosporine and are found inside of cells. The role of cyclophillins in cells is not fully understood, but these receptors may play a role in infections with viruses such as HIV and HCV. By impairing the activity of these receptors, HCV cyclophillin inhibitors can reduce the ability of HCV-infected cells to produce new viruses. Alisporivir (being developed by Novartis) is an example of a cyclophillin inhibitor.

There are other classes of anti-HCV drugs under development but they are not as far advanced as those previously mentioned.

Future Approaches to Therapy

In the treatment of HIV infection, using a combination of drugs from several classes is now the norm. Combining classes reduces the risk of HIV developing resistance to therapy. The same principle will likely apply to HCV.

Five years from now there should be a full suite of anti-HCV drugs available from different classes. When that happens, combination therapy for HCV might then include drugs from different classes and peginterferon-free regimens might finally be possible.

Reference
Gelman MA, Glenn JS. Mixing the right hepatitis C inhibitor cocktail. Trends in Molecular Medicine. 2010. In press.

Source