EU/3/10/820: Orphan designation for the treatment of argininosuccinic aciduria

Argininosuccinic aciduria is one of the inherited disorders known as 'urea cycle disorders', which cause ammonia to accumulate in the blood. Patients with argininosuccinic aciduria lack 'argininosuccinate lyase', one of the liver enzymes that are needed to get rid of excess nitrogen. In the absence of this enzyme, excess nitrogen accumulates in the body in the form of ammonia, which can be toxic at high levels, especially to the brain. Symptoms of the disease usually appear in the first few days of life and include lethargy (lack of energy), vomiting, loss of appetite, seizures (fits) and coma.

Argininosuccinic aciduria is a long-term debilitating and life-threatening disease that leads to mental retardation and is associated with a high mortality rate.

At the time of designation, argininosuccinic aciduria affected less than 0.02 in 10,000 people in the European Union (EU)*. This is equivalent to a total of fewer than 1,000 people, and is below the threshold 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. This represents a population of 506,500,000 (Eurostat 2010).

At the time of designation, no satisfactory methods were authorised in the EU for the treatment of argininosuccinic aciduria. Patients were advised to control their dietary intake of proteins, which are rich in nitrogen, to reduce the amount of ammonia formed in the body.

Human heterologous liver cells (for infusion) are 'somatic cell therapy products'. These are medicines that contain cells or tissues that have been manipulated to change their biological characteristics so that they can be used to cure, diagnose or prevent a disease.

This medicine is made of liver cells from a donor, which have been manipulated and then frozen for long-term storage. When the medicine is injected repeatedly into the portal vein (the vein leading to the liver) of patients with argininosuccinic aciduria, some of the liver cells it contains are expected to settle in the recipient's liver and start producing the missing liver enzyme, thus helping to alleviate the symptoms of the disease.

The effects of human heterologous liver cells (for infusion) have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with the medicine in patients with urea cycle disorders were ongoing.

At the time of submission, this medicine was not authorised anywhere in the EU for argininosuccinic aciduria 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 7 October 2010 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.