EU/3/19/2164: 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. Some patients with the syndrome have other kinds of tumours that produce ACTH, or tumours that produce excess cortisol directly.

Symptoms of Cushing's syndrome include 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 0.6 in 10,000 people in the European Union (EU). This was equivalent to a total of around 31,000 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 28), Norway, Iceland and Liechtenstein. This represents a population of 518,400,000 (Eurostat 2019).

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). The medicines Ketoconazole HRA and Signifor (pasireotide) were also authorised in the EU to treat the condition. Other medicines were authorised in EU countries to reduce the production of cortisol, including aminoglutethimide, metyrapone and mitotane.

The sponsor has provided sufficient information to show that relacorilant might be of significant benefit for patients with Cushing syndrome. In patients whose condition has not responded well to current treatments, early results show that the medicine can help to control blood pressure and blood sugar levels, which indicate a reduction in cortisol activity. This assumption will need to be confirmed at the time of marketing authorisation, in order to maintain the orphan status.
 

The excess cortisol in patients with Cushing’s syndrome exerts its effects by attaching to a receptor (target) known as the glucocorticoid receptor. Relacorilant also attaches to this receptor, reducing cortisol’s ability to do so, which relieves the symptoms of Cushing’s syndrome.

The effects of relacorilant have been evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials with relacorilant in patients with Cushing’s syndrome were ongoing.

At the time of submission, relacorilant was not authorised anywhere in the EU for the treatment of Cushing’s syndrome. Orphan designation of relacorilant had been granted in the United States for the treatment of endogenous Cushing’s syndrome.

In accordance with Regulation (EC) No 141/2000, the COMP adopted a positive opinion on 17 April 2019, 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.