EU/3/12/965: Orphan designation for the treatment of 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 'central' 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.

At the time of designation, Cushing's syndrome affected approximately 0.9 in 10,000 people in the European Union (EU). This was 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.
At the time of designation, this represented a population of 509,000,000 (Eurostat 2012).

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 or prevent it from working, including metyrapone, aminoglutethimide and mitotane.

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.

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.

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

Ketoconazole has been authorised in several EU countries since 1980 for the treatment of fungal skin infections.

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 January 2012 recommending the granting of this designation.

Update: Ketoconazole (Ketoconazole HRA) has been authorised in the EU since 19 November 2014 for the treatment of endogenous Cushing's syndrome in adults and adolescents above the age of 12 years.

• 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.