EU/3/12/951: Orphan designation for the treatment of carbamoyl-phosphate synthase-1 deficiency

Carbamoyl-phosphate-synthase-1 deficiency is one of the inherited disorders known as 'urea-cycle disorders', which cause ammonia to accumulate in the blood. Patients with carbamoyl-phosphate-synthase-1 deficiency lack 'carbamoyl-phosphate synthase', 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.

Carbamoyl-phosphate-synthase-1 deficiency 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, carbamoyl-phosphate synthase-1 deficiency affected less than 0.02 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 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 27), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 509,000,000 (Eurostat 2012).

At the time of designation, sodium phenylbutyrate was already authorised in the EU for the treatment of some urea-cycle disorders, including carbamoyl-phosphate-synthase-1 deficiency. This medicine is known to have a bitter taste, which may decrease compliance with treatment. In addition, 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.

The sponsor has provided sufficient information to show that this medicine might be of significant benefit for patients with carbamoyl-phosphate-synthase-1 deficiency because it is a new tasteless granule formulation of sodium phenylbutyrate developed to mask its bitter taste, which is expected to help patients to follow their treatment. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

After it is ingested, sodium phenylbutyrate is converted into a substance called phenylacetate in the body. Phenylacetate attaches to the amino acid glutamine, which contains nitrogen, forming a substance that is eliminated in the urine. This allows the levels of nitrogen in the body to decrease, reducing the amount of ammonia produced.

This medicine is a new formulation of sodium phenylbutyrate in which the granules are coated in a way that masks the bitter taste of the medicine, making it more palatable.

The effects of sodium phenylbutyrate have been evaluated in experimental models.

At the time of submission of the application for orphan designation, no clinical trials with the medicine in patients with carbamoyl-phosphate-synthase-1 deficiency had been started.

At the time of submission, this medicine was not authorised anywhere in the EU for carbamoyl-phosphate-synthase-1 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 7 December 2011 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.