EU/3/17/1867: Orphan designation for the treatment of ornithine transcarbamylase deficiency

Ornithine transcarbamylase deficiency is one of the inherited disorders known as urea-cycle disorders, which cause ammonia to build up in the blood. Patients with ornithine transcarbamylase deficiency lack ornithine transcarbamylase, one of the liver enzymes needed to get rid of excess nitrogen. In the absence of this enzyme, 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 may appear in the first few days of life (particularly in boys) and include lethargy (lack of energy), vomiting, loss of appetite, seizures (fits) and coma, often leading to death. However, the age at which symptoms start is highly variable, particularly in females.

Ornithine transcarbamylase deficiency is a long-term debilitating and life-threatening disease that can alter brain function and is associated with poor overall survival.

At the time of designation, ornithine transcarbamylase deficiency affected approximately 0.1 in 10,000 people in the European Union (EU). This was equivalent to a total of around 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 515,700,000 (Eurostat 2017).

At the time of designation, glycerol phenylbutyrate (Ravicti) and sodium phenylbutyrate (Ammonaps, Pheburane) were authorised in the EU for the treatment of some urea-cycle disorders, including ornithine transcarbamylase 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 the medicine might be of significant benefit for patients with ornithine transcarbamylase deficiency because laboratory studies show that it reduces ammonia in the blood and improves orotic aciduria, a sign of urea-cycle disorders. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

The medicine consists of genetic material (messenger RNA) containing the instructions that liver cells need to make the missing enzyme, ornithine transcarbamylase. The genetic material is enclosed in fatty particles to protect it and it is injected with another substance to help it enter liver cells. Giving the medicine by infusion (drip) into a vein every 7 to 14 days is expected to enable liver cells to produce ornithine transcarbamylase and so reduce the symptoms caused by its deficiency.

The effects of the medicine 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 ornithine transcarbamylase deficiency had been started.

At the time of submission, the medicine was not authorised anywhere in the EU for ornithine transcarbamylase deficiency. Orphan designation of the medicine had been granted in United States for ornithine transcarbamylase deficiency.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 15 March 2017 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.