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Gilead Caspase Inhibitor for Liver Disease
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Meeting Report - The 4th International Workshop on Clinical Pharmacology of Hepatitis Therapy - written by Jennifer J. Kiser, Pharm.D - (07/12/09)
Caspase Inhibitor for NASH: GS9450 is a caspase 8 and 9 inhibitor under development for nonalcoholic steatohepatitis (NASH). In vitro experiments suggested the drug had pH-dependent stability, but GS9450 did not interact with esomeprazole (a proton-pump inhibitor) in healthy volunteers. Since patients with NASH can also have type II diabetes mellitus, a drug-drug interaction study was also performed in healthy volunteers with the anti-diabetic agent glyburide. Following a single dose of glyburide, GS9450 increased glyburide Cmax an average of 23% (range 16-31%), but AUC was unchanged. The mechanism and clinical significance of this interaction are unknown. Glyburide is a substrate for the human organic anion transporting polypeptide 1B1 (OATP1B1) transporter and metabolized primarily by CYP2C9, with CYP3A4 playing a minor role. Studies to better characterize the pharmacology of GS9450 are ongoing, and may elucidate a potential mechanism for the observed interaction.
Safety, Tolerability, and Pharmacokinetics of GS-9450 in Healthy ...
This suggests that caspase inhibitors may be therapeutically useful in these diseases. GS-9450 was found to be a very potent inhibitor of caspase activity ...
www.natap.org/2009/EASL/EASL_46.htm
Gilead Reports on HCV Pipeline
FOSTER CITY, Calif., Jan 27, 2009
Advancing Therapy for Liver Disease
GS 9450, Gilead's lead product candidate for serious liver disease, is a novel, once-daily caspase inhibitor for inflammatory and fibrotic conditions including HCV and nonalcoholic steatohepatitis (NASH). NASH is a disease characterized by liver inflammation caused by a buildup of fat in the liver. The condition has been linked to obesity, high cholesterol and diabetes, and the National Center of Infectious Diseases predicts that by 2025 more than 25 million Americans may be affected.
* A Phase IIa study assessing the safety, tolerability, efficacy and pharmacokinetics of GS 9450 in HCV-infected patients has now been completed. Data from this study will be presented at a medical meeting this year, and Gilead anticipates initiating a Phase IIb study in the second quarter of the year.
* A Phase IIa study of GS 9450 in NASH patients was initiated in the third quarter of 2008 to assess the compound's safety, tolerability, efficacy and pharmacokinetics. Results from this study are expected in the fourth quarter of 2009.
* Gilead is also evaluating a novel polymerase inhibitor, GS 9190, as a potential treatment for HCV. A Phase II study of GS 9190 when combined with peg-interferon alfa 2a and ribavirin in HCV-infected patients (genotype 1) is now underway.
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