A4250 is developed for severe orphan cholestatic liver diseases, including Progressive familial intrahepatic cholestasis (PFIC), and Non-alcoholic steatohepatitis (NASH)
A4250 is an inhibitor of the ileal bile acid transporter (IBAT, syn. apical sodium-dependent bile acid transporter ASBT). Usually bile excreted into the small bowel is being reused by a transport mechanism in which bile acids are absorbed in the distal part of the small bowel. A4250 decreases this re-absorption and will reduce the toxic levels of bile acids in the diseases described above.
PFIC is a rare disease (estimated to affect more than 3000 patients in the US and 10.000 patients in the European Union) caused by a genetic defect impairing the transport of bile acids thereby inducing toxic levels of bile acid products in the liver inducing severe symptoms such as debilitating itching and scarring of the liver (cirrhosis) early in life. Although milder forms exist, most patients will develop symptoms in early childhood. Without any treatment, PFIC will lead to cirrhosis by age 10-20 years. In addition to supportive measures, the most common therapeutic modality is a surgical procedure thereby a portion of the bile production is either diverted to a stoma bag or by intestinal bypass to the large bowel. If the patient does not get better, or if there is evidence of liver cancer, then liver transplantation may be needed. There are no pharmacological treatments approved for PFIC.
Nonalcoholic steatohepatitis or NASH is a common liver disease with high unmet medical need. It is estimated that 25% of Americans, or 6 to 16 million individuals, suffer from this disease, of which an estimated 600,000 have been identified as having severe liver disease. The major feature in NASH is fat in the liver, along with inflammation and damage of the liver and is the fastest growing cause of liver transplantation in the US. There are no pharmacological treatments approved for NASH.