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.
