EU/3/19/2166: 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 5,200 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 518,400,000 (Eurostat 2019).

At the time of application for orphan designation, Ravicti (glycerol phenylbutyrate) was authorised in the EU to manage urea cycle disorders, when the diseases cannot be managed by changes in diet alone. Ammonaps and Pheburane (sodium phenylbutyrate) were also authorised to treat patients with urea-cycle disorders.

The sponsor has provided sufficient information to show that the medicine might be of significant benefit for patients with carbamoyl-phosphate synthase-1 deficiency. Data from the scientific literature have shown that the medicine can improve patients ’survival when used in emergency situations to treat acute hyperammonaemia (sudden rise of blood ammonia levels), which can occur despite ongoing long-term treatment with the authorised medicines.

This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.
 

The medicine is made up of two substances, sodium phenylbutyrate and sodium benzoate, which work by combining with glycine and glutamine, two amino acids (the building blocks of proteins) which contain nitrogen. The combination products are then removed through the urine. This can lower the amount of nitrogen in the body and so reduce the amount of waste ammonia produced. By reducing the amount of ammonia in the body, the medicine is expected to reduce its harmful effects on the brain.

The effects of the medicine 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 carbamoyl-phosphate synthase-1 deficiency had finished.

At the time of submission, the medicine was not authorised anywhere in the EU for the treatment of carbamoyl-phosphate synthase-1 deficiency.

In the United States, orphan designation of the medicine had been granted for the treatment of acute hyperammonaemia. At the time of submission, the medicine was authorised in this country (under the name Ammonul) for the treatment of acute hyperammonaemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle.

In accordance with Regulation (EC) No 141/2000, the COMP adopted a positive opinion on 29 April 2019, recommending the granting of this designation.

Opinions on orphan medicinal product designations are based on the following three criteria:

• 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.