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Orphan designation

On 17 December 2010, orphan designation (EU/3/10/821) was granted by the European Commission to Cytonet GmbH & Co. KG, Germany, for human heterologous liver cells (for infusion) for the treatment of carbamoyl-phosphate synthase-1 deficiency.

A marketing authorisation for this medicine (Heparesc) was refused on 22 October 2015.

The sponsorship was transferred to Promethera Biosciences, Belgium, in June 2016.

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 less than 0.02 in 10,000 people in the European Union (EU)*. This is equivalent to a total of fewer than 1,000 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. 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 human heterologous liver cells (for infusion) might be of significant benefit for patients with carbamoyl-phosphate synthase-1 deficiency because it works in a different way to existing treatment and early studies indicate that it might improve the treatment of patients with this condition. 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?

Human heterologous liver cells (for infusion) are ‘somatic cell therapy products’. These are medicines that contain cells or tissues that have been manipulated to change their biological characteristics so that they can be used to cure, diagnose or prevent a disease.

This medicine is made of liver cells from a donor, which have been manipulated and then frozen for long-term storage. When the medicine is injected repeatedly into the portal vein (the vein leading to the liver) of patients with carbamoyl-phosphate synthase-1 deficiency, some of the liver cells it contains are expected to settle in the recipient’s liver and start producing the missing liver enzyme, thus helping to alleviate the symptoms of the disease.

What is the stage of development of this medicine?

The effects of human heterologous liver cells (for infusion) have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with the medicine in patients with urea cycle disorders were ongoing.

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 7 October 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>Human heterologous liver cells (for infusion)</p>
Active substanceHuman heterologous liver cells (for infusion)
Medicine Name
Disease/conditionTreatment of carbamoyl-phosphate synthase-1 deficiency
Date of decision17/12/2010
Orphan decision numberEU/3/10/821

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:

Promethera Biosciences
11 Rue Granbonpré
1435 Mont-Saint-Guibert
Tel. +32 (0)10 394 304
Fax +32 (0)10 394 301

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.