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Two New HCV Drugs - NS5b and NS4b NNRTI Inhibitors- in Early Research by Genelabs/Novartis
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Genelabs Technologies, Inc. (Nasdaq: GNLB) today announced that its hepatitis C drug development and commercialization collaboration with Novartis (NYSE:NVG) is continuing to the next phase.
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In September 2006, Genelabs and Novartis entered into a two-year collaboration to discover and develop certain non-nucleoside inhibitors of the NS5b polymerase in HCV. Genelabs was responsible for drug discovery research and Novartis is responsible for development and commercialization. The research phase of the collaboration was completed on June 2, 2008. Genelabs and Novartis will continue to hold joint research committee meetings to monitor the progress of compounds discovered during this phase as they advance.
Genelabs Technologies, Inc. (Nasdaq: GNLB) today announced that its hepatitis C drug development and commercialization collaboration with Novartis (NYSE:NVG) is continuing to the next phase.
In September 2006, Genelabs and Novartis entered into a two-year collaboration to discover and develop certain non-nucleoside inhibitors of the NS5b polymerase in HCV. Genelabs was responsible for drug discovery research and Novartis is responsible for development and commercialization. The research phase of the collaboration was completed on June 2, 2008. Genelabs and Novartis will continue to hold joint research committee meetings to monitor the progress of compounds discovered during this phase as they advance.
Genelabs Technologies Announces Presentation of Data on Non-Nucleoside HCV Polymerase Inhibitor at 3rd International Workshop on Hepatitis C, Resistance and New Compounds
June 6, 2008 9:00 AM EDT
REDWOOD CITY, Calif.--(BUSINESS WIRE)--
Genelabs Technologies, Inc. (Nasdaq: GNLB) announced that a presentation was made today at the 3rd International Workshop on Hepatitis C, Resistance and New Compounds in Boston, Mass. on a non-nucleoside hepatitis C virus (HCV) polymerase inhibitor discovered by Genelabs.
The oral presentation was given by Jill Bechtel, Ph.D. entitled, "In vitro antiviral activity and resistance profile of GL60667 (NVP-LDI133), a potent non-nucleoside inhibitor of HCV NS5B polymerase." The presentation contains studies performed by both Genelabs and Novartis scientists in connection with a license and research collaboration commenced in June 2006 between Novartis and Genelabs, covering Genelabs' non-nucleoside HCV polymerase inhibitors.
GL60667 is one of a number of non-nucleoside HCV polymerase inhibitors discovered by Genelabs. In the presentation, Dr. Bechtel outlined the ability of GL60667 in vitro to reduce HCV RNA levels after prolonged (20 day) treatment, described combination HCV treatment studies with other HCV agents, and characterized the resistance profile of GL60667.
The treatment of replicon cells with 0.56 uM and 2.8 uM GL60667 for 20 days resulted in a 4-5 log reduction in HCV viral RNA. In addition, combination studies showed GL60667 was additive with interferon (alpha) or ribavirin in inhibiting HCV replication, whereas the combination with an NS3 protease inhibitor or a nucleoside NS5b inhibitor was synergistic. Sequencing of the resistant clones isolated from GL60667 selection revealed an NS5b mutation previously identified as a site for resistance to earlier compounds in this series. Interestingly, several clones had no mutations in the NS5b region. Sequencing of the entire replicon revealed several amino acid changes in NS3, NS4a, NS4b and NS5a. Transient assays using replicons bearing these mutations demonstrated that an amino acid change in the NS3 helicase domain reduced the susceptibility to GL60667 by 6.7 fold. Additional experiments demonstrated that this mutation only shifted the potency of a select number of compounds in this series leading to the identification of the region of the molecule responsible for the resistance.
"The data presented today from both Genelabs and Novartis scientists demonstrate potent antiviral activity for site 1 non-nucleoside HCV polymerase inhibitors alone or in combination with other HCV agents and a favorable resistance profile," said Ronald C. Griffith, Ph.D., Genelabs' Chief Scientific Officer. "This data clearly support the further investigation of site 1 NNI inhibitors for the future treatment of HCV infection."
Genelabs Technologies Announces Presentation of Data on HCV NS4b Inhibitors at the Inaugural HCV Drug Discovery Meeting
April 30, 2008 9:00 AM EDT
REDWOOD CITY, Calif.--(BUSINESS WIRE)--
Genelabs Technologies, Inc. (Nasdaq: GNLB) announced today that a presentation was made at the Inaugural HCV Drug Discovery meeting being held in La Jolla, California, providing information about Genelab's first-in-class program targeting a novel antiviral mechanism for treating hepatitis C virus (HCV).
The oral presentation was given by Christopher D. Roberts, Ph.D., Senior Director of Medicinal Chemistry at Genelabs, entitled "Targeting HCV NS4b Function: A New Approach to Anti-HCV Activity."
NS4b is an HCV protein that is believed to function by driving the formation of the "membranous web," the cellular scaffolding assembled by the virus in infected liver cells that is necessary for viral replication. Dr. Roberts outlined the discovery of compounds from an HCV replicon screen. Subsequently, HCV mutant replicons were raised that were resistant to these compounds and displayed consistent amino acid changes localized to a well-defined region of NS4b. "We believe that interfering with the assembly of this critical viral scaffolding can result in potent anti-HCV activity," said Dr. Roberts.
Multiple series of potent, proprietary compounds have resulted from the optimization efforts to date. The most active compounds display HCV replicon EC50 potencies under 100 nanomolar in both genotypes 1a and 1b, the most prevalent and difficult to treat HCV genotypes. Importantly, these NS4b compounds were also tested in combination with other classes of HCV antiviral compounds, including a NS5b polymerase nucleoside chain terminator, a NS5b polymerase non-nucleoside allosteric inhibitor, a NS3a protease inhibitor and interferon alpha, and shown to be additive in activity with each. When the HCV replicon was dosed for three weeks with an NS4b compound, the viral load was dropped by approximately 4 logs. Finally, in-vitro and in-vivo pharmacokinetic analyses demonstrated that compounds from this class have the potential to be well absorbed when dosed orally.
"With the clear threat of emerging viral resistance there remains the need to continue to discover and develop HCV treatments with novel mechanisms of action," said Ronald C. Griffith, Ph.D., Genelabs' Chief Scientific Officer. "Our NS4b program clearly fits this profile and our initial results show that this approach yields highly potent and orally bioavailable compounds that could play an important role in future HCV therapy. Future treatments for HCV are likely to involve combinations of antiviral drugs, and these data suggest that combinations of this new agent with interferon or other potential therapeutic drugs, such as nucleoside chain terminators, non-nucleoside inhibitors or protease inhibitors, may be feasible."
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