EU/3/07/470: Orphan designation for the treatment of ornithine-transcarbamylase deficiency

Ornithine-transcarbamylase deficiency is congenital error of metabolism that causes hyperammonaemia (abnormally high levels of ammonia in the blood). The disease is usually much milder in females than in males, because it is caused by a damaged gene on the X chromosome. As females have two X chromosomes, the normal gene on the other chromosome usually compensates the damage. Males however have only one X chromosome, so if the gene is damaged there is no compensation. As ammonia cannot be eliminated easily, it accumulates in the body. Ammonia is a toxic compound for the brain and leads to neurological damage depending on the duration and degree of hyperammonaemia. The condition is chronically debilitating and life-threatening.

Liver transplantation may be used in these patients. Liver transplantation refers to a procedure in which a failed liver is removed from the patient's body and liver tissue from a healthy donor is transplanted into the same location. The procedure is the most common method used to transplant livers. However, liver transplantation is a complex operation with important surgical risks and is often associated with significant postoperative mortality. At the time of submission of the application for orphan drug designation, other methods of treatment of acute liver failure were authorised in the Community.

Human heterologous liver cells (for infusion) might be of potential significant benefit for the treatment of ornithine-transcarbamylase deficiency because they might improve the long-term outcome of the patients. The assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

According to the information provided by the sponsor, ornithine-transcarbamylase deficiency was considered to affect less than 5,000 persons in the European Union.

*Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed based on data from the European Union (EU 27), Norway, Iceland and Lichtenstein. This represents a population of 498,000,000 (Eurostat 2006). This estimate is based on available information and calculations presented by the sponsor at the time of the application.

Liver cells differ from other cells in the sense that they are specialised to perform certain specific functions. The heterologous cells come from donors different to the person who will receive the cells. It is planned to isolate and treat these liver cells in such a way that they become able to be used for infusion into patients suffering from ornithine-transcarbamylase deficiency. The mechanism of action is not clear; it is believed that the human heterologous liver cells (for infusion) when administered to the patient, will give support to the liver functions.

At the time of submission of the application for orphan designation, the evaluation of the effects of human heterologous liver cells (for infusion) in experimental models was ongoing; clinical trials in patients with acute liver failure were also ongoing.

Human heterologous liver cells (for infusion) were not authorised anywhere in the world for acute liver failure, or designated as orphan medicinal product elsewhere for this condition, at the time of submission.

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted on 25 July 2007 a positive opinion recommending the grant of the above-mentioned designation.

• the seriousness of the condition,
• the existence or not of alternative methods of diagnosis, prevention or treatment and
• either the rarity of the condition (considered to affect not more than five in ten thousand persons in the Community) or the insufficient return of development investments.

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