EU/3/08/610

On 6 February 2009, orphan designation (EU/3/08/610) was granted by the European Commission to PPD Global Ltd, United Kingdom, for Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, (L)-malate salt for the treatment of medullary thyroid carcinoma.

The sponsorship was transferred to TMC Pharma Services Ltd, United Kingdom, in August 2011.

What is medullary thyroid carcinoma?

Thyroid carcinoma is a disease in which cancer (malignant) cells are found in certain tissues of the thyroid. The thyroid is a gland in the neck that is composed of mainly two different cell types: the follicular and parafollicular cells. The so-called follicular cells help to concentrate iodine and produce thyroid hormones. These hormones are important for the body’s growth and metabolism. The parafollicular cells produce a hormone called calcitonin that reduces calcium level in the blood. Depending on the type of cell in which the cancer cells originate, different types of thyroid cancer exist.

Medullary thyroid carcinoma originates from the parafollicular cells (also called C cells), and represents only 5-9% of all thyroid cancers. Signs of cancer are difficult to detect in early stages of the disease and are often limited to a single local swelling of the thyroid gland which is not painful but can be felt by touching. Patients are frequently diagnosed when the disease has spread locally giving symptoms such as shortness of breath, difficulties in swallowing or changes in the voice. Some patients may have severe diarrhoea as a first sign of the disease.

Medullary thyroid carcinoma is a life-threatening disease.

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

At the time of designation medullary thyroid carcinoma affected less than 0.7 in 10,000 people in the European Union (EU) *. This is based on the information provided by the sponsor and knowledge of the Committee for Orphan Medicinal Products (COMP). This is below the threshold for orphan designation which is 5 in 10,000. This is equivalent to a total of around 35,000 people.

*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 Liechtenstein. This represents a population of 502,282,000 (Eurostat 2008).

What treatments are available?

The treatment consists of a complete surgical removal of the thyroid. When patients can no longer be managed by surgery alone, various treatment approaches are tried. At the time of submission of the application for orphan drug designation, another medicine, doxorubicin, was authorised for the treatment of thyroid cancer in Sweden.

The sponsor has provided sufficient information to show that cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, (L)-malate salt might be of significant benefit for the patients because it might improve the long-term outcome of these patients. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

How is this medicine expected to work?

Enzymes are proteins produced by the human body that speed up the transformation of certain substances into other substances. Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, (L)-malate blocks (inhibits) a certain class of enzymes called tyrosine kinases. These enzymes play 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 cells. In medullary thyroid carcinoma, the function of some of these enzymes is disturbed causing uncontrolled growth and multiplication of the cancer cells. By inhibiting this enzyme activity, the product might help in slowing down or stopping the further growth of the cancer cells.

What is the stage of development of this medicine?

The effects of cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, (L)-malate salt have been evaluated in experimental models.

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

At the time of submission, the medicinal product was not authorised anywhere in the world for medullary thyroid carcinoma or designated as orphan medicinal product elsewhere for this condition.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 10 December 2008 recommending the granting of this designation.

Opinions on orphan medicinal product designations are based on the following three 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 five in 10,000 people in the Community) or the 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 the quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.