EU/3/13/1216: 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, bile acids, essential components of bile (a fluid produced by the liver which helps digestion), build up in liver cells, 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 a long-term debilitating and life-threatening condition because, when the disease progresses, it may lead to liver cirrhosis and liver failure, and may increase the risk of liver cancer.

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 was equivalent to a total of 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 28), Norway, Iceland and Liechtenstein. This represents a population of 512,200,000 (Eurostat 2013).

At the time of orphan designation, no satisfactory treatments were authorised in the EU for progressive familial intrahepatic cholestasis. Several medicines were used to treat the itching. Patient with end-stage liver disease would undergo liver transplantation.

The medicine is expected to reduce the amount of bile acid in the liver. It is expected to do so by interfering with the process by which most bile acids in the intestines are recovered and delivered back to the liver through the blood.

This medicine is thought to act locally on the intestines, blocking certain channels called ileal bile acid transporters through which the bile acids leave the intestine to reach the blood vessels that carry them back to the liver. By blocking these channels, the medicine is expected to help reduce the amount of bile acids in the liver, thereby reducing the liver damage and itching seen in patients with progressive familial intrahepatic cholestasis.

At the time of submission of the application for orphan designation, the evaluation of the effects of the medicinal product 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 6 November 2013 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.