EU/3/17/1850: 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 this condition lack a liver enzyme (ornithine transcarbamylase) needed to remove excess nitrogen. In patients without 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. The age of onset is highly variable, particularly in females.

Ornithine transcarbamylase deficiency is a long-term debilitating and life-threatening disease.

At the time of designation, ornithine transcarbamylase 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 515,700,000 (Eurostat 2017).

At the time of designation, sodium phenylbutyrate (Ammonaps) and glycerol phenylbutyrate (Ravicti) 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 this medicine might be of significant benefit for patients with ornithine transcarbamylase deficiency. Because of its mode of action, a single dose of the product is thought to produce long-term improvements. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

This medicine is made up of a virus that contains the gene for producing ornithine transcarbamylase, which the patient lacks. When given by injection, it is expected that the virus will carry the gene into the patient's liver cells and allow the patient to start producing the missing enzyme and thereby relieve symptoms of the disease.

The virus used in this medicine ('adeno-associated virus') does not cause disease in humans.

At the time of submission of the application for orphan designation, the evaluation of the effects of the medicine in experimental models was ongoing.

At the time of submission, 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 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 February 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.