EU/3/14/1314: Orphan designation for the treatment of ATP-binding cassette transporter A1 deficiency

ATP-binding cassette transporter A1 (ABCA1) is a protein that regulates the movement of cholesterol and other fatty substances out of cells. The cholesterol removed from the cells then attaches to specific fatty molecules containing a substance called apolipoprotein A-I, forming particles of 'high-density lipoprotein', or HDL. The cholesterol found in HDL particles is commonly referred to as 'good' cholesterol. These particles are then transported to the liver where they can be broken down and the cholesterol removed from the body.

In patients with ABCA1 deficiency, the ABCA1 protein is not produced in significant amounts due to a mutation (defect) in their ABCA1 genes, and so cholesterol is not effectively transported out of the cells and does not attach to the fatty molecules containing apolipoprotein A-I. This results in very low levels of HDL particles in the blood and in damaging build-up of cholesterol in blood vessels, nerves, liver, skin, gut and eyes.

ABCA1 deficiency is a long-term debilitating and life-threatening condition due to the cholesterol deposits in organs and tissues, particularly the arteries (atherosclerosis), where it increases the risk of heart disease.

At the time of designation, ABCA1 deficiency affected less than 0.01 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 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 28), Norway, Iceland and Liechtenstein. This represents a population of 511,100,000 (Eurostat 2014).

No satisfactory methods of treatment were authorised in the EU for ABCA1 deficiency at the time of designation. Patients were usually managed with measures such as a low-fat diet and medicines to lower lipids (fats) in the blood.

In patients with ABCA1 deficiency cholesterol does not leave the cells in sufficient amounts and therefore HDL particles are not adequately formed.

The medicine contains replacement HDL-like particles containing apolipoprotein A-I in a form that absorbs cholesterol very efficiently. By absorbing efficiently cholesterol that is present in the blood, this medicine is expected to facilitate the loss of cholesterol from tissues where it has been accumulating, particularly in the walls of blood vessels.

The apolipoprotein A-I in this medicine is made by a method known as 'recombinant DNA technology': it is made by cells that have received a gene (DNA) that makes them able to produce the apolipoprotein.

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

At the time of submission of the application for orphan designation, clinical trials with this medicine in patients with ABCA1 deficiency were ongoing.

At the time of submission, this medicine was not authorised anywhere in the EU for ABCA1 deficiency 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 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.