EU/3/16/1706: 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-1, one of the liver enzymes 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 harmful 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, often leading to death. However, some affected individuals may reach adulthood prior to diagnosis.

Carbamoyl-phosphate synthase-1 deficiency is a long-term debilitating and life-threatening disease that leads to altered brain function and is associated with a high mortality rate.

At the time of designation, carbamoyl-phosphate synthase-1 deficiency affected less than 0.1 in 10,000 people in the European Union (EU). This was equivalent to a total of fewer than 5,000 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 28), Norway, Iceland and Liechtenstein. This represents a population of 513,700,000 (Eurostat 2016).

At the time of designation, sodium phenylbutyrate (Ammonaps, Pheburane) and glycerol phenylbutyrate (Ravicti) were authorised in the EU for the treatment of some urea-cycle disorders, including carbamoyl-phosphate synthase-1 deficiency. 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. Liver transplantation was used to manage the condition in some people.

The sponsor has provided sufficient information to show that sodium benzoate might be of significant benefit for patients with carbamoyl-phosphate synthase-1 deficiency because its use together with currently authorised treatments may lead to improved effects. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

Sodium benzoate has been used as an unlicensed treatment for hyperammonaemia (high levels of ammonia in the blood).

It works by combining with the amino acid glycine, which contains nitrogen, to form a substance that can be removed from the body by the kidneys. This allows the levels of nitrogen in the body to decrease, reducing the amount of ammonia produced and therefore the damage to the brain and other organs.

At the time of submission of the application for orphan designation, no clinical trials with sodium benzoate in patients with carbamoyl-phosphate synthase-1 deficiency had been started. The sponsor presented data from the published literature on the use of sodium benzoate in urea cycle disorders.

At the time of submission, sodium benzoate 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 16 June 2016 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.