EU/3/07/474: Orphan designation for the treatment of cystic fibrosis

Cystic fibrosis is an inherited disease. Cystic fibrosis is caused by abnormalities of a specific gene called CFTR. Cystic fibrosis appears only when the CFTR gene is abnormal on both chromosomes of the seventh pair (one inherited from the father, the other from the mother). In cystic fibrosis, defects of the CFTR gene decrease production of a protein that regulates outflow of water and ions (like chloride) from the cells that line the internal and external surfaces of the body, the so-called epithelial cells. This defective transport of water and salts results in the thickening of the secretions (mucus) in several organs, including the lungs and the pancreas. In turn, this leads to chronic and acute infections of the lungs, chronic inflammation (a body response to the injury caused to the tissue), and digestive difficulties. In the long term, these events can induce damage to the lung tissue and the disease becomes life-threatening.

At the time of submission of the application for the orphan drug designation, lung infection and inflammation in cystic fibrosis was treated mainly with antibiotics. These can be taken in a number of ways such as through the mouth, through a vein or they can be inhaled as a fine mist of particles. Associated treatments included daily exercise and physical therapies and several other types of medications such as pancreatic enzymes and food supplements. Bronchodilators are medications that can enlarge the airways. Mucolytics help to make the secretions thinner. Other medications were also used to fight the inflammation. Alpha-1 proteinase inhibitor (inhalation use) might be of potential significant benefit for the treatment of cystic fibrosis because it can act in a different way than other available medicines. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain orphan status.

According to the information provided by the sponsor, cystic fibrosis was considered to affect about 65,000 persons in the European Union.

*Disclaimer: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed based on data from the European Union (EU 27), Norway, Iceland and Lichtenstein. This represents a population of 498,000,000 (Eurostat 2006). This estimate is based on available information and calculations presented by the sponsor at the time of the application.

Alpha-1 proteinase inhibitor (also known as alpha-1 antitrypsin) is derived from the blood of human donors. This protein has the role of inactivating some harmful substances produced by the body itself, called neutrophil elastases, which are usually involved in the inflammation. In cystic fibrosis, due to the chronic inflammation, there is an excess of these elastases in the lung, contributing to the damage of the lung tissue. By local administration of additional alpha-1 proteinase inhibitor (via inhalation) it is expected that the accumulation of this harmful elastases wil be reduced, thereby slowing down the progression of the lung disease.

The effects of alpha-1 proteinase inhibitor (inhalation use) were evaluated in experimental models. At the time of submission of the application for orphan designation, no clinical trials in patients with cystic fibrosis had been initiated.

Alpha-1 proteinase inhibitor (inhalation use) was not authorised anywhere in the world for treatment of cystic fibrosis, or designated as orphan medicinal product elsewhere for this condition, at the time of submission.

According to Regulation (EC) No 141/2000 of 16 December 1999, the Committee for Orphan Medicinal Products (COMP) adopted on 25 July 2007 a positive opinion recommending the grant of the above-mentioned designation.

• the seriousness of the condition,
• the existence or not of alternative methods of diagnosis, prevention or treatment and
• either the rarity of the condition (considered to affect not more than five in ten thousand persons in the Community) or the insufficient return of development investments.

Designated orphan medicinal products are still investigational products which were considered for designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of the quality, safety and efficacy will be necessary before this product can be granted a marketing authorisation.