EU/3/02/128

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Orphan designation

On 3 February 2003, orphan designation (EU/3/02/128) was granted by the European Commission to Enact Pharma plc, United Kingdom, for carboxypeptidase G2 for the adjunctive treatment in patients at risk of methotrexate toxicity.
The sponsorship was transferred to Protherics PLC, United Kingdom, in December 2004.

What is methotrexate toxicity?

Cancer occurs when cells grow too rapidly and in an uncontrolled way. For cancer cells to grow, new DNA needs to be made. Methotrexate is a drug that is used to treat certain cancers. With methotrexate, cancer cells can no longer make DNA. This kills cancer cells. However, methotrexate can also be harmful to other normal cells and organs in the body. This harmful effect is called methotrexate toxicity. The longer methotrexate stays in the body, the higher the risk of toxicity. Kidneys are organs in the body that filter waste matters from the blood and produce urine. Methotrexate is normally filtered by the kidney. However, if the kidney is damaged, then methotrexate may concentrate in the blood and in the whole body. This leads to further general toxicity, and further damage to the kidney,
in a vicious cycle. Methotrexate toxicity is a life-threatening condition.

What are the methods of treatment available?

There are already methods of treatment available for methotrexate toxicity. The drug folinic acid is one of these. Folinic acid has been authorised in the Community for the treatment of the condition. Many patients improve with the available treatments. However, these are not sufficient for some patients. In that case, complex medical procedures, called haemodialysis, become necessary. These very heavy procedures aim to filter methotrexate from the blood. Carboxypeptidase G2 might be an additional treatment in patients at risk of methotrexate toxicity. Satisfactory argumentation has been submitted by the sponsor to justify the assumption that carboxypeptidase G2 might be of potential significant benefit for the adjunctive treatment in patients at risk of methotrexate toxicity, particularly based on the novel mechanism of action. The assumption of benefit is yet to be validated and the benefit of carboxypeptidase G2 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 at risk of developing the condition*?

According to the information provided by the sponsor, methotrexate toxicity was considered to affect about 11,300 patients in the European Union.

*Disclaimer: The number of patients affected by the condition is estimated and assessed for the purpose of the designation, for a European Community population of 377,000,000 (Eurostat 2001) and may differ from the true number of patients affected by the condition. 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?

Carboxypeptidase G2 is a protein that can transform methotrexate into harmless substances. Thus, the amount of methotrexate in blood is lowered, and the risk of toxicity is reduced.

What is the stage of development of this medicinal product?

At the time of submission of the application for orphan designation, clinical trials in patients at risk of methotrexate toxicity were ongoing. 

Carboxipeptidase G2 was not marketed anywhere worldwide for methotrexate toxicity or designated as orphan medicinal product elsewhere for this condition, at the time of submission. 

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted on 13 December 2002 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>Carboxypeptidase G2</p>
Active substanceCarboxypeptidase G2
Medicine Name
Disease/conditionAdjunctive treatment in patients at risk of methotrexate toxicity
Date of decision03/02/2003
OutcomePositive
Orphan decision numberEU/3/02/128

Review of designation

Related information

Sponsor’s contact details:

Protherics PLC
The Heath Business and Technical Park
Runcorn
Cheshire WA7 4QF
United Kingdom
Telephone: +44 20 72 46 99 50
Telefax: +44 20 73 29 59 24
E-mail: voraxazeinfo@protherics.com