A4250 is developed for severe orphan cholestatic liver diseases, e.g. Primary biliary Cirrhosis (PBC), Progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome.
A4250 belongs to a class of inhibitors of the ileal bile acid transporter (IBAT, syn. apical sodium-dependent bile acid transporter ASBT) and is a very potent molecule with the capacity to virtually be a total inhibitor of the IBAT with a minimal systemic exposure. 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. By using a specialized delivery technology, the bile acids will be neutralized in the large bowel. The A4250 program is ready to be moved into clinical studies.
PBC is a slowly progressive autoimmune disease of the liver, primarily affecting women; average age when symptoms start is around 40-50 years of age. It is characterized by destruction of bile ducts resulting in an increased bile acid concentration in the liver inducing inflammation and cirrhosis. There are more than 100.000 patients with PBC in Europe. Main symptoms are fatigue, severe itching and symptoms of cirrhosis. There is no cure for PBC, some therapeutic alternatives may slow disease progression and relieve symptoms but some patients may need liver transplantation.
PFIC is a rare disease (estimated prevalence at birth 1/50.000 corresponding to more than 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 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.
Alagille syndrome is an inherited disease in which the patient has fewer than the normal number of bile ducts leading to increased concentration of bile acids in the liver which induce damage to the liver cells. The estimated number of patients with Alagille syndrome in the European Union is approximately 10.000-20.000. Jaundice, severe itching and growth problems are caused by the liver failure. Approximately 75% of the children diagnosed with Alagille syndrome live to 20 years of age; deaths most often caused by liver failure or heart complications.