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Orphan designation

On 5 March 2012, orphan designation (EU/3/12/971) was granted by the European Commission to Fresenius Medical Care Deutschland GmbH, Germany, for heterologous human adult liver-derived stem cells 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 a high mortality rate.

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

At the time of designation, carbamoyl-phosphate synthase-1 deficiency affected approximately 0.003 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 150 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 27), Norway, Iceland and Liechtenstein. This represents a population of 506,300,000 (Eurostat 2011).

What treatments are available?

At the time of designation, sodium phenylbutyrate, sodium phenylacetate and sodium benzoate were authorised in the EU for the treatment of some urea cycle disorders, including carbamoyl-phosphate synthase-1 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. The only cure for the disease was liver transplantation.

The sponsor has provided sufficient information to show that this medicine might be of significant benefit for patients with carbamoyl-phosphate synthase-1 deficiency because early studies show that it might improve the treatment of patients by re-establishing a normally functioning urea cycle. 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?

This medicine is made up of stem cells derived from the liver of an adult donor (‘heterologous’). Stem cells can develop into different types of cell. When implanted into the liver of a patient, it is believed that these heterologous liver-derived stem cells will develop into mature, healthy liver cells that can produce the carbamoyl-phosphate synthase enzyme. The new cells are thereby expected to restore the normal urea cycle and to relieve the symptoms of the disease.

What is the stage of development of this medicine?

At the time of submission of the application for orphan designation, the evaluation of the effects of heterologous human adult liver-derived stem cells in experimental models was ongoing.

At the time of submission, no clinical trials with the medicine in patients with carbamoyl-phosphate synthase-1 deficiency had been started.

At the time of submission, this medicine was not authorised anywhere in the EU for carbamoyl-phosphate synthase-1 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 11 January 2012 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>Heterologous human adult liver-derived stem cells</p>
Active substanceHeterologous human adult liver-derived stem cells
Medicine Name
Disease/conditionTreatment of carbamoyl-phosphate synthase-1 deficiency
Date of decision05/03/2012
Orphan decision numberEU/3/12/971

Review of designation

The Committee for Orphan Medicinal Products reviews the orphan designation of a product if it is approved for marketing authorisation.

Sponsor’s contact details:

Fresenius Medical Care Deutschland GmbH
Else-Kröner-Straße 1
61352 Bad Homburg v.d. Höhe
Telephone: +49 61 726 092417
Telefax: +49 6172 609 2381

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.