EU/3/05/325: Orphan designation for the treatment of cystic fibrosis

Cystic fibrosis is a genetic disease. Genes located on structures (the so-called chromosomes) carry the genetic information that determines the characteristics of each individual. In humans, each cell has 23 pairs of chromosomes. For each pair, one chromosome is inherited from the mother, and the other from the father. Cystic fibrosis is caused by abnormalities of a specific gene, called CFTR, carried by the seventh pair of chromosomes. Cystic fibrosis appears only when the CFTR gene is abnormal on both chromosomes of the seventh pair. The CFTR gene is responsible for the production of a protein that regulates the outflow of water and salts (like chloride) from cells that cover internal and external surfaces of the body, the so-called epithelial cells. The defective transport of water and salts, due to the lack of the regulatory protein, results in the thickening of the secretions (mucus) in several organs (e.g. lungs, pancreas). This leads to reduced functioning, chronic infection of the lungs and chronic inflammation (a body response to the injury caused to the tissue). In the long run, these events can induce damage to the lung tissue and the disease can become life-threatening.

At the time of designation, cystic fibrosis affected approximately 1.3 in 10,000 people in the European Union (EU). This was equivalent to a total of around 61,000 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 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 25), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 466,600,000 (Eurostat 2005).

At the time of submission of the application for the orphan-drug designation, lung infection and inflammation in cystic fibrosis were treated mainly with antibiotics. These can be taken in a number of ways such as through the mouth or 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 lumen of the airways. Mucolytics help to dissolve the secretions. Still other medications were used to fight the inflammation.

Mannitolum might be of potential significant benefit for the treatment of cystic fibrosis because it might improve the long-term outcome of patients. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Mannitolum is a well known, naturally occurring sugar alcohol found in most vegetables. In this medicinal product mannitolum is prepared as a dry powder for inhalation. Mannitolum is an osmotic agent, which means that it can promote the flow of liquids across membranes. In cystic fibrosis patients, this medicinal product could have an effect on the physical properties of mucus and the volume (depth) of the airway surface fluid and thus facilitate the clearance of airway secretions.

The evaluation of the effects of inhaled mannitolum is ongoing in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with cystic fibrosis were ongoing.

Mannitolum was not authorised anywhere worldwide for cystic fibrosis or designated as orphan medicinal product elsewhere for this condition, at the time of submission.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 9 September 2005 recommending the granting of this designation.

Update: Mannitolum (Bronchitol) was authorised in the EU on 13 April 2012 for the treatment of cystic fibrosis in adults aged 18 years and above as an add-on therapy to best standard of care.

• the seriousness of the condition,
• the existence of alternative methods of diagnosis, prevention or treatment and
• either the rarity of the condition (affecting not more than 5 in 10,000 people in the European Union) 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.