EU/3/09/683: Orphan designation for the treatment of inborn errors in primary bile acid synthesis responsive to treatment with cholic acid

Inborn errors in primary bile acid synthesis are a group of diseases in which the liver does not produce ('synthesise') enough 'primary bile acids'. These acids are the main components of the bile, a fluid that helps digestion, and include cholic acid and chenodeoxycholic acid. The lack of bile acids is caused by inborn genetic abnormalities.

Patients lacking primary bile acids produce abnormal bile acids instead. These acids can damage the liver. In some cases, this can lead to liver failure. Not all errors in primary bile acid synthesis can be treated with cholic acid. Therefore, patients with these conditions can be divided into two groups, depending on whether they are responsive to treatment with cholic acid or not.

Inborn errors in primary bile acid synthesis responsive to treatment with cholic acid are a group of long-term debilitating and life-threatening diseases because they can severely damage the liver.

At the time of designation, inborn errors in primary bile acid synthesis responsive to treatment with cholic acid affected approximately 0.07 in 10,000 people in the European Union (EU). This was equivalent to a total of around 3,500 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. At the time of designation, this represented a population of 504,800,000 (Eurostat 2009).

At the time of designation, no satisfactory methods were authorised in the EU for the treatment of inborn errors in primary bile acid synthesis responsive to treatment with cholic acid. Patients with severe liver disease may need a liver transplant. Chenodeoxycholic acid and another bile acid called ursodeoxycholic acid, although authorised for other conditions, were used to treat inborn errors in primary bile acid synthesis.

Cholic acid is expected to work by replacing some of the missing bile acids in patients with inborn errors in primary bile acid synthesis. This is expected to decrease the production of abnormal bile acids and contribute to the normal activity of bile acids, therefore relieving the symptoms of these diseases.

The sponsor of this application has not conducted any studies with cholic acid. However, it provided the results of studies on the effects of cholic acid in experimental models and of clinical trials from the published literature to support its application for orphan designation.

At the time of submission, cholic acid was not authorised anywhere in the EU for inborn errors in primary bile acid synthesis responsive to treatment with cholic acid. Orphan designation of cholic acid had been granted in the EU and the United States of America for inborn errors in primary bile acid synthesis.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 2 September 2009 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 Community) 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.