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.
Related research:
Stakeholder Insight: Hepatitis in China - Liver Let Die? priced $15,200
Pipeline Insight: Hepatitis C - Small Molecules, Big Revolution? priced
$11,400
Pipeline Insight: Hepatitis B - New Kids on the Block priced $11,400
