EU/3/08/556: Orphan designation for the treatment of 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.

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).

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.

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.

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.

• 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.