Direct-acting Oral Hepatitis C Drugs Nearing Approval / IL28B Recognized as Key to Hepatitis C Outcomes

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Direct-acting Oral Hepatitis C Drugs Nearing Approval

Research continues apace on novel direct-acting antiviral agents to treat

hepatitis C virus (HCV) infection. Two HCV protease inhibitors, telaprevir and

boceprevir, are poised to exit the development pipeline first, and one or both

of them may be approved in 2011.

At the American Association for the Study of Liver Diseases meeting (AASLD 2010)

this fall, researchers presented results from the Phase 3 ADVANCE and ILLUMINATE

trials, demonstrating that adding Vertex Pharmaceuticals' HCV NS34A protease

inhibitor telaprevir to pegylated interferon/ribavirin improved sustained

response rates for previously untreated genotype 1 patients, enabling many to

reduce treatment duration to 24 weeks. In late November, Vertex announced that

it has completed its submission of study data to the U.S. Food and Drug

Administration (FDA) in support of telaprevir's New Drug Application and has

request a 6-month priority review.

Findings from the Phase 3 RESPOND-2 and SPRINT-2 studies, presented at the same

meeting, showed that adding Merck's experimental HCV NS3 protease inhibitor

boceprevir to standard therapy (pegylated interferon plus ribavirin) increased

the likelihood of sustained virological response in both previously untreated

and treatment-experienced genotype 1 patients.

While targeted medications will initially be used in combination with pegylated

interferon, researchers have begun testing combinations of direct-acting agents

that affect different steps of the HCV lifecycle, for example a protease

inhibitor plus a polymerase or NS5A inhibitor (e.g., Bristol-Myers Squibb's

BMS-650032 + BMS-790052, Gilead's GS-9256 + GS-9190, and Boehringer Ingelheim's

BI 201335 + BI 207127). Such an approach may ultimately allow hepatitis C

patients to dispense with interferon and its attendant side effects and cost. In

addition, a growing body of evidence suggests that ribavirin can help improve

the likelihood of sustained response to direct-acting agents, even without

interferon.

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IL28B Recognized as Key to Hepatitis C Outcomes

HCV genotype is a well-known predictor of response to interferon-based therapy,

but it is now clear that human gene patterns are equally important.

In 2009 researchers first reported that genetic polymorphisms or natural

variations in the IL28B gene, which encodes interferon lambda, are associated

with spontaneous clearance of HCV and good response to interferon. The most

commonly reported favorable gene pattern (rs12979860 C/C) is more common among

people of European descent, helping explain why blacks do not respond as well to

treatment.

Several reports in 2010 added to the growing body of knowledge about IL28B. At

CROI 2010 several researchers reported that IL28B variations also predict

spontaneous clearance and treatment response in HIV/HCV coinfected patients. At

AASLD 2010 investigators reported that IL28B polymorphisms may also play a role

in liver disease progression; some studies found that the unfavorable rs12979860

T/T gene pattern was associated with worse liver fibrosis, although others did

not see this link. Another pair of recent studies showed that IL28B variations

may also help predict favorable outcomes after liver transplantation. Finally,

researchers have explored whether IL28B gene patterns influence outcomes and

treatment response among people with hepatitis B, but conflicting data indicate

that the association is not as straightforward as it is for hepatitis C.