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Combination Drugs Are The Future for Hepatitis C


Xconomy San Diego — 

Combination therapy has been a central component of treatment for certain viral diseases for more than 15 years. The benefits of combination therapy can arise from activation of multiple host pathways, suppression of mutational variants that can lead to viral escape, or perhaps both.

In HIV, the benefit of combination therapy is due to suppression of viral resistance, which is the result of using multiple agents acting at distinct sites within the virus life cycle. In hepatitis C (which I’ll abbreviate as HCV) the addition of ribavirin to interferon turned what was primarily an on-treatment lowering of viral titers into the first significant rate of viral clearance that persisted even after therapy was stopped. This sustained virological response, known as SVR, has become the primary measurement of clinical benefit in HCV. The mechanism underlying the dramatic effect of combining ribavirin with interferon is not clear. The benefit could be due to a pharmacologic interaction between pathways activated by interferon and pathways activated by ribavirin, or it may be the result of a modest ribavirin antiviral effect added to an “antiviral state” induced by interferon.

Just this year, companies in the HCV field began exploring the use of direct antiviral combinations. It is hoped that by appropriately choosing complementary targets, benefits of combination similar to what was seen in HIV may soon be seen in HCV therapy. Whether or not the combination of direct antivirals will permit the elimination of interferon and/or ribavirin remains unknown at this time, and is perhaps the most highly anticipated answer in the HCV field today.

Combinations of antivirals today

Three companies have moved into the clinical stage of exploring direct antiviral combinations for HCV.

Roche is most advanced in combination studies of direct antivirals with its INFORM-1 study. In this study, HCV patients were treated for 14 days with various dose levels of two drug candidates that inhibit different parts of the virus life cycle. These drug candidates are RG7128, a nucleoside polymerase inhibitor licensed from Pharmasset, and RG7227, a protease inhibitor licensed from Intermune. Data from the first several dosing cohorts was disclosed this past April at the annual meeting of the European Association for the Study of the Liver. Additional data, including responses at higher doses and in patients who previously failed interferon/ribavirin, will is being reported at the annual meeting of the American Association for the Study of Liver Diseases conference in Boston.

The INFORM-1 study clearly shows that two antiviral agents can act in concert to produce a greater antiviral effect over 14 days than either agent produced alone. At the same time, critical questions remain for longer studies — Can direct antivirals alone retain viral titers at undetectable levels over longer periods of treatment? Even more important, will a state of virus negativity elicited by a direct antiviral combination afford the same rate of SVR once therapy is stopped as when virus negativity is induced by the interferon/ribavirin combination? Is there anything special about the mechanism(s) relied upon to reach negativity, or once arrived at, are all virus negativities created equal?

Two other companies have taken the first steps toward a combination study of two direct antivirals in HCV patients. Gilead Sciences has conducted a study in healthy volunteers to assess any interactions between a non-nucleoside polymerase inhibitor and a protease inhibitor (GS-9190 and GS-9256 respectively). Likewise, Vertex Pharmaceuticals is conducting a similar study using the same two classes of therapeutics. This study includes telaprevir, a protease inhibitor currently in late stage clinical trials, and VX-222, a non-nucleoside Vertex gained through its acquisition of ViroChem earlier this year. For both of these companies, assessing interactions between the drugs preludes studying these combinations in HCV patients.

Standard of care plus antivirals

In addition to the clinical trials testing combinations of two direct antivirals, drug developers are expected to test combinations of two direct antivirals with pegylated interferon and/or ribavirin, with various objectives for various trial designs.

In patients who have not been previously treated, there is a possibility that treatment with two antivirals added to interferon/ribavirin may further increase SVR beyond that seen when a single antiviral was added to interferon/ribavirin, although a more likely outcome is an increase in the percentage of patients who can successfully be treated with shorter course interferon.

In patients who previously failed to achieve SVR on interferon/ribavirin, the situation may be different. Vertex’s PROVE 3 clinical trial showed that adding a single antiviral on top of interferon/ribavirin enhanced SVR rates, but with plenty of room for further improvement. In this case, adding a second direct antiviral to create a four drug combination may indeed improve SVR. There is also interest in testing the ability to remove interferon and/or ribavirin through the use of two direct antivirals.

Many trial designs to test combinations involving multiple direct antivirals have been discussed. There will be a significant advantage to companies who have access to the agents required to conduct such combination trials and whose trial design creativity is coupled to effective interactions with regulatory agencies such that they can efficiently move through the complex space of potential trials to arrive at optimum combination regimens.

Impact on biotech business

The benefits of combinatorial therapy may drive significant business activity as well. As the HIV field approached combination clinical trials in the early 1990s, it became clear that the challenge of getting two or more sponsors who owned individual drug candidates to agree to specific trial designs represented a significant hurdle to moving forward. Cooperative groups such as AIDS Clinical Trials Group (ACTG) and government sponsored trials struggled to provide efficient paths to combination trials.

Gilead Sciences utilized a business combination to solve this puzzle. By acquiring Triangle Pharmaceuticals in 2003, for approximately $460 million, the company gained access to the product FTC. On its own, FTC was a thoroughly undifferentiated product. However, by controlling the asset Gilead could efficiently develop combinations with its attractive agent tenofovir, which ultimately led to the fixed dose combination products tenofovir emtricitabine (Truvada) and tenofovir emtricitabine efavirenz (Atripla). Many would argue that the acquisition of Triangle was a critical step in Gilead’s path to its current market cap of approximately $40 billion.

In HCV, the first business combination directed at clinical exploration of antiviral combinations was seen earlier this year when Vertex acquired ViroChem for approximately $375 million.

The medical community will watch closely as companies test antiviral combinations, and the investment community will watch closely to see which companies are most adept at establishing compelling combination regimens, and to see if the need for assets to create combinations leads to additional combinatorial business activity.

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  • Three drug combo very interesting. Sounds like the future treatment for HCV. My husband is post-transplant and wishes to try the three drug combo, but we have been turned down by everyone that would be expected or could help in paying for the teleprivir or Incivek. Are you aware of any post transplant clinical trials being done with the 3 drug combo? Thanks, Barbara Miracle