EU/3/13/1163: 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 this disorder lack 'argininosuccinate lyase', one of the liver enzymes that are needed to get rid of excess nitrogen. In the absence of this liver 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 approximately 0.19 in 10,000 people in the European Union (EU). This was equivalent to a total of around 10,000 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 27), Norway, Iceland and Liechtenstein. This represents a population of 509,000,000 (Eurostat 2013).

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.

This medicine is an advanced-therapy medicine that belongs to the group called '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. The medicine is made up of progenitor (immature) cells derived from the liver of an adult donor ('heterologous'). When implanted into the liver of a patient, it is believed that these heterologous liver-derived progenitor cells will develop into mature, healthy liver cells that can produce the argininosuccinate lyase enzyme. The new cells are thereby expected to reduce the accumulation of ammonia and to relieve the symptoms of the disease.

The effects of heterologous human adult liver-derived progenitor cells 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, the medicine was not authorised anywhere in the EU for argininosuccinic aciduria. Orphan designation of the medicine had been granted in the United States for urea-cycle disorders.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 13 June 2013 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.