EU/3/12/965 - orphan designation for treatment of Cushing's syndrome

Ketoconazole

Overview

On 23 April 2012, orphan designation (EU/3/12/965) was granted by the European Commission to Laboratoire HRA Pharma, France, for ketoconazole for the treatment of Cushing's syndrome.

Ketoconazole has been authorised in the EU as Ketoconazole HRA since 19 November 2014.

The sponsorship was transferred to HRA Pharma Rare Diseases, France in December 2019.

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 '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.

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 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 isbased on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

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*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).

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 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.

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 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.

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.

EU/3/12/965: Public summary of opinion on orphan designation: Ketoconazole for the treatment of Cushing’s syndrome

AdoptedReference Number: EMA/COMP/66372/2012 Rev. 1

Key facts

• Active substance:
  Ketoconazole
• Medicine name:
  Ketoconazole HRA
• Intended use:
  Treatment of Cushing's syndrome
• Orphan designation status:
  Expired
• EU designation number:
  EU/3/12/965
• Date of designation:
  23/04/2012
• Sponsor:

  HRA Pharma Rare Diseases; 200 avenue de Paris; 92320 Chatillon; France; Tel: [phone]; E-mail: [e-mail]

Review of designation

During its meeting of 7 to 9 October 2014, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/12/965 for Ketoconazole HRA (ketoconazole) as an orphan medicinal product for the treatment of Cushing's syndrome. The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other methods of treatment. As other methods of treatment are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with Cushing's syndrome. The COMP recommended that the orphan designation of the medicine be maintained*.

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The maintenance of the orphan designation at time of marketing authorisation would, except in specific situations, give an orphan medicinal product 10 years of market exclusivity in the EU. This means that in the 10 years after its authorisation similar products with a comparable therapeutic indication cannot be placed on the market.