EU/3/10/733

On 10 June 2010, orphan designation (EU/3/10/733) was granted by the European Commission to Hyperion Therapeutics Limited, United Kingdom, for glyceryl tri-(4-phenylbutyrate) for the treatment of carbamoyl-phosphate synthase-1 deficiency.

What is 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 poor overall survival.

What is the estimated number of patients affected by the condition?

At the time of designation, carbamoyl-phosphate synthase-1 deficiency affected approximately 0.14 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 7,000 people, and is below the threshold 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. This represents a population of 506,500,000 (Eurostat 2010).

What treatments are available?

At the time of designation, phenylbutyrate was authorised in the EU for the treatment of some urea cycle disorders, including carbamoyl-phosphate synthase-1 deficiency. This medicine was available as tablets and granules. 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 glyceryl tri-(4-phenylbutyrate) might be of significant benefit for patients with carbamoyl-phosphate synthase-1 deficiency because the medicine would be available as an oil that has almost no taste or smell. This is expected to make the medicine easier for patients to take, because it is more palatable than phenylbutyrate tablets or granules. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

How is this medicine expected to work?

Glyceryl tri-(4-phenylbutyrate) is a ‘prodrug’ of phenylbutyrate. It consists of three molecules of phenylbutyrate linked together. After it is swallowed, the medicine is expected to be broken down into phenylbutyrate in the gut. Phenylbutyrate works by being converted into phenylacetate in the body and combining with the amino acid glutamine, 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.

What is the stage of development of this medicine?

The effects of glyceryl tri-(4-phenylbutyrate) have been evaluated in experimental models.

At the time of submission of the application for orphan designation, a study with glyceryl tri-(4-phenylbutyrate) in patients with urea cycle disorders had been completed.

At the time of submission, glyceryl tri-(4-phenylbutyrate) was not authorised anywhere in the EU for carbamoyl-phosphate synthase-1 deficiency. Orphan designation of glyceryl tri-(4-phenylbutyrate) had been granted in the United States of America for the maintenance treatment of patients with deficiencies in enzymes of the urea cycle.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 3 February 2010 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.