EU/3/10/736

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Orphan designation

On 10 June 2010, orphan designation (EU/3/10/736) was granted by the European Commission to Hyperion Therapeutics Limited, United Kingdom, for glyceryl tri-(4-phenylbutyrate) for the treatment of argininosuccinic aciduria.

For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.

What is argininosuccinic aciduria?

Argininosuccinic aciduria is one of the inherited disorders known as ‘urea cycle disorders’, which cause ammonia to accumulate in the blood. Patients with argininosuccinic aciduria lack ‘argininosuccinate lyase’, 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.

Argininosuccinic aciduria 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, argininosuccinic aciduria affected approximately 0.07 in 10,000 people in the European Union (EU). This was equivalent to a total of around 4,000 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. At the time of designation, this represented a population of 506,300,000 (Eurostat 2010).

What treatments are available?

At the time of designation, no satisfactory methods were authorised in the EU for the treatment of argininosuccinic aciduria. 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.

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 argininosuccinic aciduria. 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.

Key facts

Product details for <p>Glyceryl tri-(4-phenylbutyrate)</p>
Active substanceGlyceryl tri-(4-phenylbutyrate)
Medicine Name
Disease/conditionTreatment of argininosuccinic aciduria
Date of decision10/06/2010
OutcomePositive
Orphan decision numberEU/3/10/736

Review of designation

Sponsor’s contact details

Hyperion Therapeutics Limited
90 Long Acre, Covent Garden 
London WC2E 9RZ 
United Kingdom
Tel. +44 (0)650 745 7820
Fax +44 (0)650 745 1021
E-mail: klara.dickinson@hyperiontx.com

Patients' organisations

For contact details of patients’ organisations whose activities are targeted at rare diseases, see:

  • Orphanet, a database containing information on rare diseases, which includes a directory of patients’ organisations registered in Europe;
  • European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.