La Jolla Pharmaceutical Company, a leader in the development of therapeutics that target galectin-3, has demonstrated the results of a mouse study examining the effect of GCS-100 on liver fibrosis. When compared to placebo-treated control animals La Jolla's lead product, GCS-100, showed a statistically significant reduction in liver fibrosis, a statistically significant improvement in the Non-Alcoholic Fatty Liver Disease ("NAFLD") score and a statistically significant improvement in liver function as measured by the liver enzyme alanine transaminase ("ALT"), in some cases returning to near normal levels.
The study was performed in collaboration with the Stelic Institute & Co. (Tokyo, Japan) using an established, benchmark preclinical STAM model for Non-alcoholic Steatohepatitis-hepatocellular carcinoma (NASH-HCC).
The National Institute of Diabetes and Digestive and Kidney Diseases states that NASH affects between seven million and 17.5 million Americans. In addition, an estimated 5.5 million Americans have chronic liver disease or cirrhosis. Together chronic liver disease and cirrhosis are currently the 12th leading cause of death, accounting for approximately 27,000 deaths annually, in the United States. Chronic Liver disease affects Americans of all ages and walks of life.
In the 12-week STAM model, NASH is established in mice by a single subcutaneous injection of streptozotocin (Sigma, USA) after birth, followed by the feeding of a high fat diet ad libitum after four weeks of age. NASH develops at about week seven with evidence of fibrosis at week nine and liver nodule formation at week 11-12. In the present study, mice were randomized at nine weeks of age into three groups: a treated group which received 1 mg/kg GCS-100 IV, a treated group which received 25 mg/kg GCS-100 IV, and a control group which received inactive placebo. All animals received their respective administrations three times per week during weeks nine-12. At the end of the 12 weeks, blood and tissue samples were collected and analyzed for liver enzymes, NAFLD activity score, and presence of fibrosis by microscopic inspection. Animals in the high-dose GCS-100 treatment group showed a statistically significant improvement in all 3 of these efficacy measures.
"The results of this study demonstrate that GCS-100 is able to prevent and potentially reverse chronic liver disease through the remediation of fibrosis," said James Rolke, Senior Director of Research and Development at La Jolla. "In addition, the significant improvement in liver function and NAFLD suggests a preservation of functional tissue which is a clear clinical objective and benefit."
Overall the treatment of GCS-100 in STAM mice was well tolerated. The whole blood and plasma biochemistry results showed GCS-100 treatment decreased plasma ALT, but had no effect on blood glucose levels. Additionally, liver biochemistry showed GCS-100 decreased the amount of hydroxyproline present. Histological analysis showed a significant improvement in NAFLD score with decreased micro- and macrovesicular fat deposition, hepatocyte ballooning and inflammatory cell infiltration. Lastly, GCS-100 treated animals showed a significant decrease in the fibrosis area as measured by Sirius red staining.
"We are very pleased to see positive results from this preclinical study supporting the therapeutic role of GCS-100 in liver fibrosis," said George Tidmarsh, M.D. Ph.D., President and Chief Executive Officer of La Jolla. "The liver disease program will complement our other programs with GCS-100 in chronic organ failure. Patients with chronic liver disease are in need of novel therapies to treat this terrible affliction and we plan to soon file an IND with FDA for the treatment of liver disease."
GCS-100 is a complex polysaccharide that has the ability to bind to and block the effects of galectin-3. Galectin-3 is a soluble protein, over-expression of which has been implicated in a number of human diseases including cancer and chronic organ failure. The unique ability of GCS-100 to bind and sequester galectin-3 makes it an ideal candidate to prevent and treat diseases in which galectin-3 plays an important role.
La Jolla Pharmaceutical Company is a biopharmaceutical company dedicated to the development of medical treatments that significantly improve outcomes in patients with life-threatening diseases.