• Email
  • Help

Orphan designation

On 8 July 2008, orphan designation (EU/3/08/556) was granted by the European Commission to Voisin Consulting S.A.R.L., France, for N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide for the treatment of cystic fibrosis.

The sponsorship was transferred to Vertex Pharmaceuticals (U.K.) Limited, United Kingdom, in August 2011 and to Vertex Pharmaceuticals (Europe) Limited, United Kingdom, in August 2015.

N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide has been authorised in the EU as Kalydeco since 23 July 2012.

What is cystic fibrosis?

Cystic fibrosis is a hereditary (genetic) disease that affects the production of secretions (such as mucus) from the glands in the body. It affects the lungs and the digestive system (gut) in particular. Cystic fibrosis is caused by abnormalities in a gene called ‘cystic-fibrosis transmembrane conductance regulator’ (CFTR). The CFTR gene is responsible for the production of CFTR, a protein that regulates the production of mucus and digestive juices by acting as a chloride-ion channel to allow proper movement of salt and water in and out of certain cells in the lungs and other tissues. In patients with cystic fibrosis, there is an overproduction of mucus in the lungs and a reduced production of digestive juices from the pancreas (an organ near the stomach). This leads to long-term infection and inflammation of the lungs and problems with the digestion and absorption of food resulting in poor growth.

Cystic fibrosis is a long-lasting and life-threatening disease.

What is the estimated number of patients affected by the condition?

At the time of designation cystic fibrosis affected approximately 1.2 in 10,000 people in the European Union (EU). This was equivalent to a total of around 60,000 people*, and is below the threshold for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and 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 502,800,000 (Eurostat 2008).

What treatments are available?

At the time of submission of the application for orphan-drug designation, lung infection and inflammation in cystic fibrosis were mainly treated with physiotherapy and antibiotics. Other medicines used to treat the lung disease included bronchodilators (medicines that help to open up the airways in the lungs) and mucolytics (medicines that help dissolve the mucus in the lungs). In addition, patients are often given other types of medicine such as pancreatic enzymes (substances that help to digest and absorb food) and food supplements. They are also advised to exercise and to undergo physiotherapy.

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide might be of potential significant benefit for the treatment of cystic fibrosis because it is expected to bring relief of the symptoms of the disease by acting in a different way to existing treatments. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

How is this medicine expected to work?

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide is thought to restore the ability of CFTR channels to transport chloride ions into and out of cells. This is intended to help maintain the proper level of salt and water on airway surfaces, reducing the formation and accumulation of mucus in the lung, and thus improving the symptoms of the disease.

What is the stage of development of this medicine?

The effects of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide have been evaluated in experimental models. At the time of submission of the application for orphan designation, clinical trials in patients with cystic fibrosis were ongoing.

At the time of submission, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide was not authorised anywhere in the world for the treatment of cystic fibrosis. Orphan designation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide had been granted in the United States for cystic fibrosis.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 14 May 2008 recommending the granting of this designation.

Update: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide (Kalydeco) was authorised in the EU on 23 July 2012 for the treatment of cystic fibrosis (CF) in patients age six years and older who have a G551D mutation in the CFTR gene.

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 Community) 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.

Key facts

Product details for <p>N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide</p>
Active substanceN-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide
Medicine NameKalydeco
Disease/conditionTreatment of cystic fibrosis
Date of decision08/07/2008
Orphan decision numberEU/3/08/556

Review of designation

During its meeting of 12 and 13 June 2012, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/08/556 for Kalydeco (ivacaftor)1 as an orphan medicinal product for the treatment of cystic fibrosis. 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 satisfactory methods of treatment. As other methods of treatment for patients with this condition are authorised in the European Union (EU), the COMP also looked at the significant benefit of the product over existing treatments. The COMP recommended that the orphan designation of the medicine be maintained2.

1At time of orphan designation, ivacaftor was known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide.
2The 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 Kalydeco for ‘the treatment of cystic fibrosis in patients aged six years and older who have a G551D mutation in the CFTR gene’.

This falls within the scope of the product’s designated orphan condition, which is ‘treatment of cystic fibrosis’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2008. Cystic fibrosis remains a condition that is life-threatening and debilitating in the long term, particularly due to the recurrent and resistant respiratory infections with development of a lung condition known as bronchiectasis. Death usually occurs from terminal respiratory failure or from haemoptysis (coughing up of blood) due to erosion of large blood vessels in the lungs.

Prevalence of the condition

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of cystic fibrosis 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 reviewed based on recent analyses and was estimated to be approximately 0.7 people in 10,000. This is equivalent to a total of around 35,000 people in the EU.

Existence of other satisfactory methods of treatment

At the time of the review of the orphan designation, other treatments were authorised in the EU for use in cystic fibrosis. They include the antibiotics Cayston and Tobi Podhaler used to treat the lung infection in cystic fibrosis and Bronchitol, an agent that facilitates the clearance of bronchial mucus.

Significant benefit over existing treatments

The COMP concluded that the claim of a significant benefit of Kalydeco in cystic fibrosis is justified on the basis of its mechanism of action. Unlike other medicines authorised for use in cystic fibrosis and associated infections, Kalydeco targets the underlying defect in the functioning of the cystic-fibrosis transmembrane conductance regulator (CFTR), a protein involved in the production of mucus and digestive juices. Its mechanism of action has been shown to translate into clinical benefits, such as improvements in lung function and a reduction in the number of pulmonary exacerbations. This constitutes a therapeutic advantage for ivacaftor in patients with the CFTR G551D mutation, when used alone or in combination with other medicines authorised for the treatment of cystic fibrosis.

Therefore, the COMP concluded that Kalydeco is of significant benefit for patients affected by cystic fibrosis.


Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Kalydeco still meets the criteria for designation as an orphan medicinal product and that Kalydeco should remain in the Community register of orphan medicinal products.

Sponsor’s contact details

Vertex Pharmaceuticals (Europe) Limited
2 Kingdom Street
London W2 6BD
United Kingdom
Tel. +44 (0)20 3204 5108
Fax +44 (0)20 3204 5220

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.