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Orphan designation

On 14 September 2007, orphan designation (EU/3/07/477) was granted by the European Commission to Interface International Consultancy Ltd , UK, for 4-Amino-1-[5-O-[(2R,4S)-2-oxido-4-(4-pyridinyl)-1,3,2-dioxaphosphorinan-2-yl]-β-D-arabinofuranosyl]-2(1H)-pyrimidinone for the treatment of hepatocellular carcinoma.

What is hepatocellular carcinoma?

Tumours that begin in the liver are known as liver tumours. Liver tumours that originate from the specific cells of the liver (hepatocytes) are called hepatocellular carcinomas. The most common factors known to be associated with this disease are viral infections that result in liver inflammation (in particular, hepatitis B and hepatitis C) and cirrhosis of the liver, particularly if induced by excessive consumption of alcohol. Hepatocellular carcinoma is a life-threatening condition.

What are the methods of treatment available?

Several medicinal products were authorised in the European Union for the treatment of hepatocellular carcinoma, at the time of the application. Surgical removal of the tumour or liver transplantation are the only chances of a cure, but are possible or indicated only in a very limited number of patients.
The medicinal product is expected to offer a potential significant benefit over existing authorised treatments as it has a different mechanism of action. The assumption of significant benefit will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

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

According to the information provided by the sponsor, hepatocellular carcinoma was considered to affect about 50,000 persons in the European Union.

* 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.

How is this medicinal product expected to act?

The product is a prodrug (a drug precursor), which means that it is not active alsone, but it is converted by the human body into the active substance, in this case into cytarabine monophosphate that is further converted to cytarabine triphosphate. Cytarabine triphosphate inhibits the growth of many tumours, but it is not normally used in the treatment of liver tumours because it is toxic for the bone marrow. 4-Amino-1-[5-O-[(2R,4S)-2-oxido-4-(4-pyridinyl)-1,3,2-dioxaphosphorinan-2-yl]-β-D-arabinofuranosyl]-2(1H)-pyrimidinone is designed to bypass the bone marrow, because as a precursor, it would undergo conversion initially to cytarabine monophosphate and ultimately cytarabine triphosphate only in the liver, and not in other tissues, including the bone marrow where most of the toxicity occurs.

What is the stage of development of this medicinal product?

The effects of the medicinal product were evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with hepatocellular carcinoma were ongoing.

The medicinal product was not authorised anywhere in the world for hepatocellular carcinoma, nor designated as orphan medicinal product for this condition, at the time of submission of the application.

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted on 24 July 2007 a positive opinion recommending the grant of the above-mentioned designation.

Opinions on orphan medicinal products designations are based on the following cumulative criteria:
  • the seriousness of the condition, 
  • the existence or not of alternative methods of diagnosis, prevention or treatment and
  • either the rarity of the condition (considered to affect not more than five in ten thousand persons in the Community) or the insufficient return of development investments.

Designated orphan medicinal products are still investigational products which were considered for designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of the quality, safety and efficacy will be necessary before this product can be granted a marketing authorisation.

Key facts

Product details for <p>4-Amino-1-[5-O-[(2R,4S)-2-oxido-4-(4-pyridinyl)-1,3,2-dioxaphosphorinan-2-yl]-&szlig;-D-arabinofuranosyl]-2(1H)-pyrimidinone</p>
Active substance4-Amino-1-[5-O-[(2R,4S)-2-oxido-4-(4-pyridinyl)-1,3,2-dioxaphosphorinan-2-yl]-ß-D-arabinofuranosyl]-2(1H)-pyrimidinone
Medicine Name
Disease/conditionTreatment of hepatocellular carcinoma
Date of decision14/09/2007
Orphan decision numberEU/3/07/477

Review of designation

Sponsor’s contact details:

Interface International Consultancy Ltd
Main Street
York YO42 1YQ
United Kingdom
Telephone: +44 1377 28 84 20
Telefax: +44 13 77 28 81 48

Patients’ associations contact points:

Ligue Nationale Contre le Cancer
13 Av. de la Grande Armee
75116 Paris
Telephone: +33 1 45 00 00 17
Tefefax: +33 1 45 00 63 06

British Liver Trust
Portman House
44 High Street
BH24 1AG
United Kingdom
Telephone: +44 14 25 46 30 80

The Association of European Cancer Leagues (ECL)
c/o Belgian Federation against Cancer
Chaussée de Louvain, 479
B-1030 Brussels
Telephone: +32 2 743 3705
Telefax: +32 2 734 9250