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Mar 15, 2009 (Vol. 29, No. 6)

Making Improvements to Standard of Care for HCV

Small Molecule Combination Therapies Are Being Investigated to Increase Response Rates

  • Click Image To Enlarge +
    Fluorescent microscopic image of cells harboring HCV replicons

    Researchers agree that now is a crucial time to be involved in hepatitis C virus (HCV) research. “Current estimates suggest that HCV infects over 170 million people worldwide,” notes David B. Smith, Ph.D., principal research scientist, Roche. “The current standard of care (SOC) for HCV involves 48–72 weeks of treatment with pegylated interferon and ribavirin. Approximately 40–60% of the patients treated with SOC achieve a sustained viral response after this treatment. Roche is highly active in the effort to discover additional treatment options that can be added to the existing SOC to increase these response rates and benefit more patients.”

    Improving the course of treatment for HCV is not without its challenges, however. “HCV has a notoriously high rate of mutation,” says Anna M. Boguszewska-Chachulska, Ph.D., cofounder of Genomed. “We need to find a solution that addresses this, and there are a few compounds under development out there that look promising at this time.”

    Cambridge Healthtech is hosting an HCV drug discovery track as a part of the “Drug Discovery Chemistry Conference” to be held next month in San Diego. This article previews some of the talks as well as provides an update on what’s happening in small molecule drug discovery in the HCV field.

  • Entry Inhibitors

    Flossie Wong-Staal, Ph.D., CSO and executive vp research at ItherX, says that the conference is happening at a good time for her company. “We just licensed a compound that failed as an anti-inflammatory that has great potential in the HCV space. It already has a good safety profile in over 250 human subjects and is highly potent against HCV entry (EC50 in the picomolar range). This drug is now ready for a proof of concept clinical study in HCV patients.

    “Our back-up candidates exhibit EC50 of <1 nM and a >10,000-fold therapeutic window in our assays has been shown using both genotype 1 and genotype 2 HCV. All the entry inhibitors act additively with the current standard of care as well as an HCV protease inhibitor,” says Dr. Staal. “Furthermore, the compounds are equally potent against a protease mutant virus that is resistant to the protease inhibitor. This class of compounds can add significantly to a drug cocktail targeting multiple steps of the viral life cycle, with the goal of completely eliminating virus infection.”

    Dr. Wong-Staal will talk about developing entry inhibitors for HCV. “We’ve developed different programs for targeting virus entry at different points. ITX5081 and its back-up compounds target a known HCV receptor, SR-B1. We have a series of compounds that target the HCV virus envelope. This is at the lead-optimization stage. A third program is based on a new receptor for HCV that we have discovered and shown to be essential for HCV infection of liver cells.

    “This target is amenable to both biologics and small molecule drug development. Unlike HIV, which utilizes one of two alternative co-receptors for virus entry, HCV engages multiple receptors in series, and it appears that blocking any of these receptors would affect virus inhibition. Furthermore, such inhibitors should be able to work synergistically with each other, as well as with inhibitors using other modes of action.”

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