EU/3/08/610

  • Email
  • Help

Orphan designation

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.

For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.

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 was equivalent to a total of fewer than 35,000 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 (EU 27), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 504,800,000 (Eurostat 2009).

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.

Update: Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, (L)-malate salt (Cometriq) has been authorised in the EU since 21 March 2014 for treatment of adult patients with progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma.

More information on Cometriq can be found in the European public assessment report (EPAR).

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.

Key facts

Product details for <p>Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, (L)-malate salt</p>
Active substanceCyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, (L)-malate salt
Medicine NameCometriq
Disease/conditionTreatment of medullary thyroid carcinoma
Date of decision05/02/2009
OutcomePositive
Orphan decision numberEU/3/08/610

Review of designation

During its meeting of 7-9 January 2014, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/08/610 for Cometriq (cabozantinib)1 as an orphan medicinal product for the treatment of medullary thyroid carcinoma. The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other methods of treatment. As other methods of treatment for patients with this condition are authorised in the European Union (EU), the COMP also looked at the significant benefit of the product over existing treatments. The COMP recommended that the orphan designation of the medicine be maintained2.


1Previously known as cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide, (L)-malate salt).
2The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation similar products with a comparable therapeutic indication cannot be placed on the market.

Life-threatening or long-term debilitating nature of the condition

The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Cometriq for:

‘treatment of adult patients with progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma’.

This falls within the scope of the product’s designated orphan indication, which is: ‘treatment of medullary thyroid carcinoma’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2009. Medullary thyroid carcinoma remains debilitating due to the major surgery needed, and is a life-threatening condition in patients whose disease cannot be treated by surgery or has spread throughout the body.

Prevalence of the condition

The sponsor informed the COMP that no literature suggestive of a change in the EU prevalence of medullary thyroid carcinoma has been published since the orphan designation was granted in 2009.

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of medullary thyroid carcinoma remains below the ceiling for orphan designation, which is 5 people in 10,000. At the time of the review of the orphan designation, the prevalence was still estimated to be less than 0.7 people in 10,000. This is equivalent to a total of fewer than 36,000 people in the EU.

Existence of other satisfactory methods of treatment

At the time of the review of the orphan designation, medullary thyroid carcinoma was primarily treated by surgical removal of the thyroid gland. Caprelsa (vandetanib) and, in Sweden, doxorubicin were authorised in the EU for the treatment of medullary thyroid carcinoma.

Significant benefit over existing treatments

The COMP concluded that the claim of a significant benefit of Cometriq in medullary thyroid carcinoma is justified on the basis of a different safety profile to existing treatments, which means that Cometriq can be used in some patients who are unsuitable for other treatments such as Caprelsa due to risks of heart problems. Additionally, Cometriq may offer a treatment option for patients for whom other treatments do not work or have stopped working: the sponsor has shown that out of 25 patients with progressive disease who had previously been given Caprelsa, 7 had a partial response when treated with Cometriq.

Therefore, although other satisfactory methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Cometriq is of significant benefit for patients affected by medullary thyroid carcinoma.

Conclusions

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that cabozantinib still meets the criteria for designation as an orphan medicinal product and that Cometriq should remain in the Community Register of Orphan Medicinal Products.

Related information

Sponsor’s contact details

TMC Pharma Services Ltd
Lodge Farm Barn
Elvetham Park Estate
Fleet Road
Hartley Wintney
United Kingdom
Tel. +44 (0)1252 842255
Fax +44 (0)1252 842277
E-mail: info@tmconsultancy.com

Patients' organisations

For contact details of patients’ organisations whose activities are targeted at rare diseases, see:

  • Orphanet, a database containing information on rare diseases which includes a directory of patients’ organisations registered in Europe.
  • European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.