EU/3/05/267: Orphan designation for the treatment of malignant gastrointestinal stromal tumours

Malignant gastrointestinal stromal tumours (GIST) are the most common subtype of gastro-intestinal sarcomas, which belong to the group of soft tissue sarcomas. Soft tissue sarcomas are cancers of the tissues that support, surround and protect the organs of the body, such as muscle tissue and fat tissue. The cause of gastrointestinal stromal tumours is largely unknown. Gastrointestinal stromal tumours are most common in the stomach (60-70%), followed by small intestine (20-30%), and colon and rectum (5%). Gastrointestinal stromal tumours occur predominantly in middle-aged and older persons and are considered as a life-threatening condition.

At the time of designation, GIST affected approximately 0.3 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 14,000 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 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 25), Norway, Iceland and Liechtenstein. This represents a population of 459,700,000 (Eurostat 2004).

The current methods of treatment are surgical removal of the tumour and treatment with a medicinal product, which belongs to the same group of substances called tyrosine kinase inhibitors, aimed at slowing down and potentially stop the tumour growth.

(Z)-N-[2-(Diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (S)-2-hydroxysyccinate could be of potential significant benefit for the treatment of malignant GIST, mainly because it could act in a different way and thereby might improve the long-term outcome of the patients. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Enzymes are proteins produced by the human body that speed up the conversion of certain substances into other substances. Z)-N-[2-(Diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (S)-2-hydroxysyccinate blocks (inhibits) the enzyme tyrosine kinase. This enzyme plays a role in a cascade of molecular reactions to bring a certain signal from outside the cell into the cell thereby controlling the growth of the cells. In cancer cells, the function of this enzyme is disturbed causing uncontrolled growth and multiplication of the cancer cells.

Z)-N-[2-(Diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (S)-2-hydroxysyccinate might, by inhibition of this enzyme activity at a certain level in the cascade, help in slowing down or stopping the further growth of the cancer cells.

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

The medicinal product was not authorised anywhere worldwide for renal cell carcinoma 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 3 February 2005 a positive opinion recommending the grant of the above-mentioned designation.

Update: (Z)-N-[2-(Diethylamino)ethyl]-5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (S)-2-hydroxysyccinate (Sutent) is authorised in the European Union as of 19 July 2006 for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance. Efficacy is based on time to tumour progression and an increase in survival.

• 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 Community) 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.