Liver Fibrosis (NASH or others)
According to the National Digestive Diseases Information Clearinghouse (NDDIC), nonalcoholic steatohepatitis (NASH) prevalence in the U.S. is 2-5%. An additional 10-20% of Americans have fat in their liver, but no inflammation or liver damage, a condition called “fatty liver.” The underlying cause of NASH is unclear, but it most often occurs in persons who are middle-aged and overweight or obese. Many patients with NASH have elevated serum lipids, diabetes or pre-diabetes. Progression of NASH can lead to liver cirrhosis. Liver transplantation is the only treatment for advanced cirrhosis with liver failure. At this time, there is no treatment for NASH.
MN-001 administered orally once daily (10, 30, and 100 mg/kg) for 3 weeks, was evaluated in the STAM™ (NASH-HCC) mouse model of nonalcoholic steatohepatitis, as measured by liver biochemistry and histopathology, NAFLD activity score (NAS), and percent of fibrosis and gene expression.
MN-001, in a dose-dependent manner, significantly reduced fibrosis area compared with vehicle (p <0.01) as demonstrated by a reduction in liver hydroxyproline content, supporting MN-001’s anti-fibrotic properties. MN-001 significantly improved NAS (p <0.01), and this was most likely attributed to the reduction in lobular inflammation and hepatocyte ballooning, the latter being most notable. Hepatocyte ballooning is thought to be derived from oxidative stress-induced hepatocellular damage and is associated with disease progression of NASH. MN-001, in this animal model, improved NASH pathology by inhibiting hepatocyte damage (p <0.01) and ballooning (p <0.01).
Congruently, MN-001 was shown to down-regulate certain gene expression levels in the liver. At low and mid doses, MN-001 significantly down-regulated MCP-1 (p <0.01) and CCR2 mRNA (p < 0.01) expression levels compared to vehicle. Similarly, MN-001 significantly down-regulated Collagen type 1 (p <0.01) and TIMP-1 mRNA (p <0.001) expression levels at low and mid doses. These gene expression data imply that MN-001 prevents the formation of fibrosis in the NASH model.
Recent preclinical results provide compelling evidence that MN-001 warrants further evaluation for the treatment of NASH in humans. MediciNova has an open IND at FDA. Due to safety data from previous clinical studies of MN-001, FDA has approved the protocol for a Phase 2 study as the first clinical trial of MN-001 in NASH.