EU/3/02/128: Orphan designation for the adjunctive treatment in patients at risk of 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.

At the time of designation, methotrexate toxicity affected approximately 0.3 in 10,000 people in the European Union (EU). This was equivalent to a total of around 11,000 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. At the time of designation, this represented a population of 382,800,000 (Eurostat 2003).

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.

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.

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.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 13 December 2002 recommending the granting of this designation.

• 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.