EU/3/11/925: Orphan designation for the treatment of hypercortisolism (Cushing's syndrome) of endogenous origin

Hypercortisolism (Cushing's syndrome) is a set of symptoms caused by an excess of the glucocorticoid hormone cortisol in the blood. The symptoms include weight gain (particularly in the face and neck), easy bruising, excessive growth of coarse hair on the face, weakening of the muscles and bones, and high blood pressure. 'Endogenous' means that the excess cortisol is caused by the body producing too much of the hormone and not by the patient taking medicines that can cause the condition. Endogenous hypercortisolism is usually caused by a tumour of the glands that are involved in the production of cortisol.

Endogenous hypercortisolism 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, hypercortisolism (Cushing's syndrome) of endogenous origin affected approximately 0.6 in 10,000 people in the European Union (EU). This was equivalent to a total of around 30,000 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 507,700,000 (Eurostat 2011).

At the time of designation, the main treatments for endogenous hypercortisolism involved treating the tumour responsible for causing the high cortisol levels, such as by surgery or radiotherapy (treatment with radiation) and using medicines to block the production of cortisol. Metyrapone was authorised in some EU countries for the management of patients with Cushing's syndrome.

The sponsor has provided sufficient information to show that mifepristone might be of significant benefit for patients with hypercortisolism (Cushing's syndrome) of endogenous origin because it works in a different way to existing medicines for endogenous hypercortisolism and may offer an alternative for patients who do not respond to currently authorised treatments. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.

Mifepristone has several medical uses. In endogenous hypercortisolism, mifepristone is expected to act as a 'glucocorticoid receptor antagonist'. This means that it blocks the receptors that 'glucocorticoids' such as cortisol normally attach to. By blocking these receptors, mifepristone prevents cortisol from working and reduces the symptoms of high cortisol levels.

The effects of mifepristone have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with mifepristone in patients with hypercortisolism (Cushing's syndrome) of endogenous origin had started.

At the time of submission, mifepristone mifepristone was not authorised anywhere in the world for the treatment of hypercortisolism (Cushing's syndrome) of endogenous origin. Orphan designation of mifepristone had been granted in the EU for hypercortisolism (Cushing's syndrome) of endogenous origin and for Cushing's syndrome secondary to ectopic ACTH secretion. In the United States, orphan designation of mifepristone had been granted for the clinical manifestations of endogenous Cushing's syndrome and for Cushing's syndrome secondary to ectopic ACTH secretion.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 16 September 2011 recommending the granting of this designation.

• 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.