EU/3/14/1308: Orphan designation for the treatment of autosomal dominant polycystic liver disease

Autosomal dominant polycystic liver disease (ADPLD) is an inherited condition in which cells in the lining of the bile ducts (the network of channels in the liver through which bile is secreted) grow and develop abnormally, forming numerous cysts (fluid-filled sacs) in the tissue of the liver.

Women are affected more than men and tend to have larger cysts. About 20% of patients with the condition develop symptoms due to the growth of these cysts, which can gradually enlarge the liver so that it presses on other organs, causing pain and preventing both the liver and the other organs from working properly. Cysts may also become twisted under pressure (torsion) leading to tissue damage or rupture, and complications due to infection or bleeding into the centre of the cyst may occur. The condition is 'autosomal dominant', which means that it is caused by gene mutations (defects) that are 'dominant' because a person can have the disease even if they have inherited a defective gene from only one parent.

ADPLD is a chronically debilitating and life-threatening condition due to failure of organs around the enlarged liver and the complications of infection, torsion and bleeding into the cyst.

At the time of designation, ADPLD affected approximately 0.02 in 10,000 people in the European Union (EU). This was equivalent to a total of around 1,000 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 511,100,000 (Eurostat 2014).

At the time of designation, no satisfactory methods were authorised in the EU for the treatment of ADPLD. Patients with symptoms were treated with supportive care and surgery to relieve the effects of cyst growth. Patients without symptoms did not require treatment.

The medicine combines a form of vitamin C, sodium ascorbate, with a form of vitamin K, menadione sodium bisulfite, both of which have been available for many years in the EU. When given together, these vitamins can interfere with the cycle of growth and development of abnormal cells, preventing them from growing. In patients with ADPLD this action of both vitamins is expected to reduce the growth of cysts and so stop enlargement of the liver and development of symptoms and complications.

The effects of the medicine have been evaluated in experimental models.

At the time of submission of the application for orphan designation, no clinical trials with this medicine in patients with ADPLD had been started.

At the time of submission, the combination of sodium ascorbate and menadione sodium bisulfite was not authorised anywhere in the EU for ADPLD. Orphan designation of the medicine had been granted in the United States for ADPLD and the related condition, autosomal dominant polycystic kidney disease.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 10 July 2014 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.