EU/3/05/298: Orphan designation for the treatment of Cushing's syndrome secondary to ectopic ACTH secretion

Cushing's syndrome is defined as a set of clinical symptoms caused by a prolonged exposure to a high concentration of a certain substance called adrenocorticotrophic hormone (ACTH). ACTH is a naturally produced hormone that stimulates the adrenal glands (two small glands located above the kidneys, in the abdomen) to secrete other hormones, the glucocorticoid hormones. ACTH is normally produced in the body by a small oval shaped gland situated at the base of the brain (pituitary gland), but can also be (over) produced by several types of tumours This abnormal production is called “ectopic ACTH secretion”. The glucocorticoids (e.g. cortisol) are substances involved in the metabolism of sugars, lipids and proteins as well as on the inflammatory and defence mechanism of the organism. The clinical symptoms of overproduction of ACTH are hypertension, body shape modifications; vascular fragility; muscular weakness and osteoporosis (a reduction in the amount of bone mass, leading to fractures after minimal trauma); diminished resistance to infection; psychiatric disorders; healing defects; gonadal dysfunction (malfunctioning of sex organs, such as ovaries or testicles); hirsutism (abnormal hairiness), female balding and acne. Cushing's disease is chronically debilitating and in some cases can be life threatening due to an overall decreased life expectancy.

Several products with anti-cortisol activity were authorised for the condition in some countries in the Community at the time of submission of the application for orphan drug designation. Mifepristone could be of potential significant benefit for the treatment of Cushing's syndrome secondary to ectopic ACTH secretion, because it might improve the long-term outcome of the patients. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

According to the information provided by the sponsor, Cushing's syndrome secondary to ectopic ACTH secretion was considered to affect less than 5,000 persons in the European Union.

*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 25), Norway, Iceland and Lichtenstein. This represents a population of 459,700,000 (Eurostat 2004). This estimate is based on available information and calculations presented by the sponsor at the time of the application.

Mifepristone is a drug that is supposed to bind to a certain structure of the cells (the cortisol receptor). By binding to these receptors, the cortisol itself cannot bind anymore and therefore it cannot exert its function anymore. Then, having blocked the receptor, it neutralises the effect of the abnormally elevated cortisol levels in Cushing's syndrome. Its action is reversible, which means that the receptor can exert its normal action after the effect of the drug stops.

At the time of submission of the application for orphan designation, no clinical trials in patients with Cushing's syndrome were planned. Mifepristone was not marketed anywhere worldwide for Cushing's syndrome secondary to ectopic ACTH secretion, at the time of submission. The medicinal product was designated as orphan medicinal product in the United States for this condition, at the time of submission. According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted on 15 June 2005 a positive opinion recommending the grant of the above-mentioned designation.

• the seriousness of the condition,
• the existence or not of alternative methods of diagnosis, prevention or treatment and
• either the rarity of the condition (considered to affect not more than five in ten thousand persons in the Community) or the insufficient return of development investments.

Designated orphan medicinal products are still investigational products which were considered for 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 will be necessary before this product can be granted a marketing authorisation.