EU/3/12/1028: Orphan designation for the treatment of progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis is an inherited condition that causes progressive liver disease, which normally leads to liver failure. In progressive familial intrahepatic cholestasis, a fluid produced by the liver called bile, which helps digestion, is not 'transported' normally to the intestine. This results in bile acids, essential components of bile, building up in liver cells and becoming toxic to the liver and causing cirrhosis (scarring). Symptoms usually begin in infancy and include severe itching, jaundice (yellowing of the skin and eyes), delayed growth, pancreatitis (inflammation of the pancreas) and bleeding inside the stomach or the gut. At later stages, high blood pressure in the vein that supplies blood to the liver and liver failure will appear.

Progressive familial intrahepatic cholestasis is chronically debilitating due to early appearance of the symptoms and liver problems. It is also life-threatening due to severe liver damage.

At the time of designation, progressive familial intrahepatic cholestasis affected not more than 0.2 in 10,000 people in the European Union (EU)*. This is equivalent to not more than 10,000 people, and is below the ceiling for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

*Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed on the basis of data from the European Union (EU 27), Norway, Iceland and Liechtenstein. This represents a population of 506,300,000 (Eurostat 2011).

At the time of orphan designation, no satisfactory treatments were authorised in the EU for this condition. Rifampicin was used to treat the itchiness, ursodeoxycholic acid was used to treat some types of progressive familial intrahepatic cholestasis and vitamin supplements were given to children to prevent deficiencies. Patient with end-stage liver disease underwent liver transplantation.

The medicine is expected to block some proteins on the surface of intestinal cells called 'ileal sodium-dependent bile-acid transporters'. These bile acid transporters are involved in the transport of bile acids from the intestines back to the liver, where they are recycled to produce more bile, a process known as 'bile-acid re-uptake'. By blocking the transporters, the medicine is expected to reduce the entry of bile acids into liver cells, and thereby prevent their accumulation and the toxicity in the liver cells. This is expected to help improve the symptoms of the disease.

At the time of submission of the application for orphan designation, the evaluation of the effects of the medicine in experimental models was ongoing.

At the time of submission, no clinical trials with the medicine in patients with progressive familial intrahepatic cholestasis had been started.

At the time of submission, the medicine was not authorised anywhere in the EU for progressive familial intrahepatic cholestasis or designated as an orphan medicinal product elsewhere for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 13 June 2012 recommending the granting of this designation.

• the seriousness of the condition;
• the existence of alternative methods of diagnosis, prevention or treatment;
• either the rarity of the condition (affecting not more than 5 in 10,000 people in the EU) or insufficient returns on investment.

Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.