REDWOOD CITY, Calif.—Biopharmaceutical company Genelabs Technologies announced it was advancing two of its drug discovery projects for testing as possible therapeutics against Hepatitis C virus (HCV). The compounds are part of a multi-pronged attack that relies on nucleoside- and non-nucleoside-based approaches.
"We believe, philosophically, that the future of HCV treatments will evolve to multiple drugs that will address multiple virus-specific targets, as is the case with HIV/AIDS therapies today," says James Smith, company president and chief executive officer. "These combination therapies may focus on polymerase inhibition or some other mechanism of virus replication, such as protease inhibition."
Initial studies of the non-nucleoside compound GL60667 showed that it was very potent against HCV replication and exhibited strong inhibition of the viral polymerase enzyme needed to produce more viruses. Furthermore, the compound targets HCV at concentrations 100 times below those that cause toxicity in human cell lines.
The success of GL60667 follows closely on the heels of another non-nucleoside compound, GL59728, which the company is moving into GLP preclinical studies. If successful, this will be the first step toward the filing of an Investigational New Drug (IND) application.
As Smith explains, part of the impetus for developing new drugs against HCV comes from the challenge that currently available therapies, which rely on a combination of alpha-interferon and the nucleoside ribavirin, are less than 50% effective in people infected with HCV genotype 1, the major viral genotype in developed countries (most prevalent in western Europe and North America) during the one-year therapeutic regimen. As the incidence of HCV infection increases—Centers for Disease Control and Prevention numbers suggest 25,000 new cases annually in the United States alone—this represents a growing population of patients and therefore an unmet medical need.
"Furthermore, current therapy is poorly tolerated, leading to flu-like symptoms, anemia, and psychiatric problems, and exhibits significant adverse drug events, so drop out rates are high," he adds. "To us, this indicated that there was significant room for improvement."
Genelabs' interest in HCV also stems from the company's longstanding interest in virus biology. According to Smith, the company was founded in 1984 to discover and better understand pathogenic viruses and how they replicate. To that end, Genelabs was instrumental in the elucidation of the Hepatitis G and Hepatitis E viruses. But in 1995, says Smith, the company made a shift to small-molecule discovery and development, focusing its attention on HCV.
"Our business model is to license out the commercial rights to compounds that we develop in-house," he says. "We take a portfolio approach so that in some cases, we sign collaboration and licensing deals earlier in development, while in other cases, the deals are signed later, after we have absorbed more risk and added more value."
In September 2004, Genelabs signed a licensing and collaborative deal with Gilead for the further development of one of its nucleoside compounds, whereby Gilead would provide research funding and the possibility of downstream royalty payments on any products that arise. With its non-nucleoside and NS5A programs, however, Genelabs decided to add value to the program and not partner until late in development.
