Vertex: next-generation hepatitis drugs within reach

Vertex has launched a major phase II clinical trial to test a new hepatitis C drug candidate, with a second trial scheduled to begin in June. This is a significant advance in the development of much-needed treatments for hepatitis C. By drawing parallels with similar HIV treatments, Datamonitor's Morris Paterson outlines the pitfalls and prospects for this new drug.

The trial will measure the effectiveness of VX-950 in combination with the current standard of care, the optimal treatment duration, and the role of ribavirin in VX-950-based therapy.

Just days before announcing the initiation of this trial, Vertex posted encouraging results from a smaller phase IIa study, in which the drug was found to be highly effective in 12 treatment-naive patients.

VX-950 belongs to a class of drugs called protease inhibitors (PIs). These drugs currently show the greatest promise as next-generation treatments for hepatitis C. The current standard of care in this indication, pegylated interferon plus ribavirin combination therapy, suffers from major drawbacks, including moderate efficacy (with a cure rate of approximately 50%), significant side effects and an inconvenient mode of administration (weekly subcutaneous injections). Patients and physicians are hoping that the next generation of drugs will be more effective, in tablet or capsule form and with fewer side effects.

Traditionally, PIs have formed an important part of antiviral drug regimes. For example, the development of PIs against HIV was an important step forward in the fight against the virus. Protease inhibitors block an enzyme involved in cleaving the viral poly-protein. This is a crucial stage in the virus' lifecycle - if this step is blocked, the virus cannot function, replicate or infect other cells.

Developing a protease inhibitor against the hepatitis C virus (HCV) has proved particularly difficult. The 3D structure of the HCV protease enzyme has posed significant challenges for drug developers. In particular, the active site of the enzyme is broader and shallower than drug makers require. Many pharmaceutical companies have run HCV PI discovery programs without success.

Schering-Plough is the only other company to have reached phase II testing with an orally available inhibitor of the HCV protease. Schering-Plough's SCH 503034 entered a phase IIa trial in September 2005, which is expected to be completed in April 2007. Interim findings from this study have not yet been published.

Despite their significance in HIV treatment, PIs have not been without their troubles. As a class, these drugs have been associated with a number of side effects, such as changes in blood sugar levels (and occasionally diabetes), elevations in blood fat levels and lipodystrophy.

In recent years, the effectiveness of HIV PIs has been increased by co-administration with low-dose ritonavir - a technique referred to as 'boosting'. Ritonavir, itself a PI, inhibits one of the pathways by which drugs are metabolized. Blocking this pathway can result in increased blood concentration of other administered drugs. This increases a PI's effectiveness and reduces the number of tablets that are required - something referred to as 'pill burden' by HIV patients and physicians. Vertex is planning a clinical study dosing VX-950 with ritonavir in HCV infected patients in the second half of 2006.

A further risk to the development of many drugs targeting viral enzymes is drug resistance. As with HIV, this is also likely to pose a major challenge to the development and clinical use of HCV PIs. In vitro studies using HCV replicons have already shown that VX-950 can induce drug resistance mutations. This is inevitable given how rapidly many viruses can mutate.

Despite the many obstacles HCV PI development faces and has faced to date, the fact remains that this market represents a sizeable commercial opportunity. Total sales of HCV drugs reached $2.1 billion in 2004 and, while this market has remained flat in recent years, Datamonitor has predicted significant growth for the near future.

This growth will be driven mainly by new drugs reaching the market and increasing public awareness, which will concomitantly increase levels of HCV diagnosis and, consequently, the number of patients seeking treatment.

If further incentive were needed, Vertex' HCV trials are also being carefully watched by investors and analysts, as the company's shares rose by more than 4% following news of the phase II trial being initiated.

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