• Email
  • Help

Orphan designation

On 9 August 2012, orphan designation (EU/3/12/1031) was granted by the European Commission to Agenzia Industrie Difesa-Stabilimento Chimico Farmaceutico Militare, Italy, for ketoconazole for the treatment of Cushing’s syndrome.

What is Cushing’s syndrome?

Cushing’s syndrome is a disease characterised by an excess of the hormone cortisol in the blood. It is usually caused by a tumour of the pituitary gland (a gland located at the base of the brain) that produces large amounts of adrenocorticotropic hormone (ACTH), which in turn stimulates the production of excess cortisol from the adrenal glands, which are situated above the kidney. Patients with Cushing’s syndrome have weight gain affecting the face and torso but not the limbs, growth of fat above the collar bone and the back of the neck, a roundish face, easy bruising, excessive growth of coarse hair on the face, weakening of the muscles and bones, depression, diabetes and high blood pressure.

Cushing’s syndrome is a severe disease that is long lasting and may be life-threatening because of its complications, including diabetes, high blood pressure and mental problems.

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

At the time of designation, Cushing’s syndrome affected approximately 0.9 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 46,000 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. This represents a population of 506,300,000 (Eurostat 2011).

What treatments are available?

At the time of designation, the main treatment for ACTH-dependent Cushing’s syndrome involved surgery to remove the tumour responsible for causing the high cortisol levels, sometimes followed by radiotherapy (treatment with radiation). Several medicines were authorised in the EU to reduce the production of cortisol, including pasireotide, trilostane and metyrapone.

The sponsor has provided sufficient information to show that ketoconazole might be of significant benefit for patients with Cushing’s syndrome because it works in a different way to existing treatments and may be used in patients who cannot undergo surgery or take other authorised medicines. These assumptions 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?

Ketoconazole is an antifungal medicine used to treat fungal skin infections. Apart from its well-known antifungal activity, studies show that ketoconazole also blocks the activity of enzymes involved in production of steroids, including cortisol. In Cushing’s syndrome, ketoconazole is expected to block the action of these enzymes, thereby reducing cortisol levels and relieving the symptoms of the disease.

What is the stage of development of this medicine?

The sponsor has provided non-clinical data from the published literature to support its application for orphan designation.

At the time of submission of the application for orphan designation, a clinical trial with ketoconazole in patients with Cushing’s syndrome was planned.

At the time of submission, ketoconazole was not authorised anywhere in the EU for Cushing’s syndrome or designated as an 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 11 July 2012 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;
  • 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.

Key facts

Product details for <p>Ketoconazole</p>
Active substanceKetoconazole
Medicine Name
Disease/conditionTreatment of Cushing’s syndrome
Date of decision09/08/2012
Orphan decision numberEU/3/12/1031

Review of designation

The Committee for Orphan Medicinal Products reviews the orphan designation of a product if it is approved for marketing authorisation.

Sponsor’s contact details

Agenzia Industrie Difesa-Stabilimento Chimico Farmaceutico Militare
Via XX Settembre 123/A
00187 Rome
Tel. +39 0554 5561
Fax +39 0554 250568

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.