EU/3/12/965

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Orphan designation

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.

For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.

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).


*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.

Name Language First published Last updated
EU/3/12/965: Public summary of opinion on orphan designation: Ketoconazole for the treatment of Cushing’s syndrome (English only) 03/05/2012 12/03/2015

Key facts

Product details for <p>Ketoconazole</p>
Active substanceKetoconazole
Medicine NameKetoconazole HRA
Disease/conditionTreatment of Cushing’s syndrome
Date of decision23/04/2012
OutcomePositive
Orphan decision numberEU/3/12/965

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*.


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.

Life-threatening or long-term debilitating nature of the condition

The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Ketoconazole HRA for: ‘treatment of endogenous Cushing’s syndrome in adults and adolescents above the age of 12 years’.

This falls within the scope of the product’s designated orphan indication, which is: ‘treatment of Cushing’s syndrome’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2012. Cushing’s syndrome remains a condition that is debilitating in the long term and life threatening, particularly because of its complications, including diabetes, clotting disorders, muscular weakness, osteoporosis and mental problems.

Prevalence of the condition

The sponsor provided recent scientific literature on the prevalence of Cushing’s disease. On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of Cushing’s syndrome remains below the ceiling for orphan designation, which is 5 people in 10,000. At the time of the review of the orphan designation, the prevalence was still estimated to be approximately 0.9 people in 10,000. This is equivalent to a total of around 46,000 people in the EU.

Existence of other methods of treatment

At the time of the review of the orphan designation, the main treatment for Cushing’s syndrome involved surgery to remove the tumour responsible for causing high cortisol levels. In patients in whom surgery does not work or cannot be used radiotherapy (treatment with radiation) or medicines can be used. Medicines authorised in the EU for the treatment of Cushing’s syndrome to reduce the production of cortisol include metyrapone, mitotane and pasireotide.

Significant benefit of Ketoconazole HRA

The COMP concluded that the claim of a significant benefit of Ketoconazole HRA in Cushing’s syndrome is justified on the basis of relevant data showing improved control of cortisol levels when ketoconazole was added to existing treatment of patients who were not completely controlled with other products currently authorised for the condition.

Therefore, although other methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Ketoconazole HRA is of significant benefit to patients affected by Cushing’s syndrome.

Conclusions

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Ketoconazole HRA still meets the criteria for designation as an orphan medicinal product and that Ketoconazole HRA should remain in the Community Register of Orphan Medicinal Products.

Related information

Sponsor’s contact details

Laboratoire HRA Pharma
15, rue Béranger
75003 Paris
France
Tel. +33 1403 31130
Fax +33 1403 31231
E-mail: regulatory@hra-pharma.com

Patients' organisations

For contact details of patients’ organisations whose activities are targeted at rare diseases, see:

  • Orphanet, a database containing information on rare diseases which includes a directory of patients’ organisations registered in Europe.
  • European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.