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Orphan designation

On 4 February 2008, orphan designation (EU/3/08/530) was granted by the European Commission to Prof Etienne Sokal, Belgium, for heterologous human adult liver derived stem cells for the treatment of ornithine-transcarbamylase deficiency.

The sponsorship was transferred to Promethera Biosciences, Belgium, in June 2010.

What is ornithine-transcarbamylase deficiency?

Ornithine-transcarbamylase deficiency is a congenital error of metabolism, which causes hyperammonemia (abnormally high levels of ammonia in the blood) because a genetic mutation renders one of the liver enzymes responsible for ammonium elimination non-functional. As ammonia cannot be eliminated easily, it accumulates in the body. Ammonia is toxic for the brain, and leads to neurological damage depending on the duration and degree of hyperammonaemia. The disease is usually milder in females than in males, because it is caused by a damaged gene on the X chromosome; as females have two X chromosomes, the normal gene on the other chromosome usually compensates the damage at least partially. Males however have only one X chromosome, so if the gene is damaged there is no compensation. The condition is chronically debilitating and life-threatening.

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

At the time of designation, Crigler-Najjar syndrome affected affect less than 0.1 in 10,000 people in the European Union (EU)*. This is equivalent to a total of fewer than 5,000 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 based on data from the European Union (EU 27), Norway, Iceland and Lichtenstein. This represents a population of 498,000,000 (Eurostat 2006). This estimate is based on available information and calculations presented by the sponsor at the time of the application.

What are the methods of treatment available?

The long-term management of the disease is based on low-protein diet to avoid excess ammonia production and pharmacological treatment to detoxify ammonium. Liver transplantation is a complex operation, with important surgical risks, and it can be associated with postoperative mortality. At the time of submission of the application for orphan drug designation, other methods of treatment of hyperammonemia were authorised in the Community. However, liver transplantation is currently the only curative treatment. Liver transplantation is a procedure in which the failed liver is removed from the patient's body, and liver tissue from a healthy donor is transplanted into the same location.

Heterologous human adult liver derived stem cells might be of potential significant benefit for the treatment of ornithine-transcarbamylase deficiency because they may improve the long-term outcome of the patients. The assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

How is this medicine expected to work?

Liver cells are able to perform certain specific functions. Heterologous human adult liver derived stem cells are stem cells isolated from the adult liver itself. Stem cells have the capacity to differentiate (to change their characteristics and capacities and acquire new specific functions) into more mature liver cells. The cells will come from a donor, not from the patient (heterologous). The mechanism of action is not fully understood but it is believed that the heterologous human adult liver derived stem cells will become mature and functional liver cells, therefore they will be able to provide the enzymes lacking in the condition.

What is the stage of development of this medicine?

The evaluation of the effects of heterologous human adult liver derived stem cells in experimental models is ongoing.

At the time of submission of the application for orphan designation, no clinical trials in patients with ornithine-transcarbamylase deficiency were initiated.

Heterologous human adult liver derived stem cells was not authorised anywhere worldwide for ornithine-transcarbamylase deficiency or designated as orphan medicinal product elsewhere for this condition, at the time of submission.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 10 October 2007 recommending the granting of this designation.

Opinions on orphan medicinal products designations are based on the following cumulative criteria:
  • the seriousness of the condition, 
  • the existence of alternative methods of diagnosis, prevention or treatment and 
  • either the rarity of the condition (affecting not more than 5 in 10,000 people in the European Union) 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&nbsp; stem cells</p>
Active substanceHeterologous human adult liver derived  stem cells
Medicine Name
Disease/conditionTreatment of ornithinine transcarbamylase deficiency
Date of decision03/02/2008
Orphan decision numberEU/3/08/530

Review of designation

Sponsor's contact details:

Promethera Biosciences
Watson & Crick Hill
11 Rue Granbonpré
1435 Mont-Saint-Guibert
Telephone: +32 10 39 43 00
Telefax: +32 10 39 43 01

Patients’ associations contact points:

Xtraordinaire: Association Nationale des Retards Mentaux liés au chromosome X
96 Rue Jules Guesdes
92130 Levallois-Perret
Telephone: +33 1 41 10 59 57

AISMME: Associazione Italiana Studio Malattie Metaboliche Ereditarie ONLUS
Via N. Tommaseo 67-c
35131 Padova
Telephone: +39 049 93 66 129