EU/3/04/204: Orphan designation for the treatment of Gram-negative bacterial lung infection in cystic fibrosis

Cystic fibrosis is an inherited disease. The genetic information that determines the characteristics of each individual is carried by genes located on structures called chromosomes. 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 7th pair of chromosomes. The CFTR gene is responsible for the production of a protein that regulates outflow of water and salts (like chloride) from cells that cover internal and external surfaces of the body, the so-called epithelial cells. Cystic fibrosis appears only when the CFTR is abnormal on both chromosomes of the 7th pair. The defective transport of water and salts due to the lack of the regulatory protein results in thickening of the secretions in several organs (e.g. lungs, pancreas). This leads to chronic infection of the lungs and chronic inflammation (a response to the injury caused to the tissue). Gram negative bacteria (primary characteristic of bacteria with a particular cell wall layer identified through staining) are micro-organisms that can cause certain types of infections. Chronic infection of the lung with gram-negative bacteria is a typical feature of cystic fibrosis. It can induce damage to the lung tissue and respiratory insufficiency, which is life threatening.

At the time of designation, gram negative bacterial lung infection in cystic fibrosis affected approximately 1.3 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 50,000 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: The number of patients affected by the condition is estimated and assessed for the purpose of the designation, for a European Community population of 385,000,000 (Eurostat 2002) and may differ from the true number of patients affected by the condition. This estimate is based on available information and calculations presented by the sponsor at the time of the application.

Gram negative bacterial lung infection in cystic fibrosis is treated mostly with antibiotics (drugs that kill micro-organisms) administered by a variety of routes, oral, intravenous and as an aerosol via nebulisation in the lungs (fine spray that the patient has to breath). Several antibiotics were authorised for the condition in some countries in the Community, at the time of submission of the application for orphan designation.

Satisfactory argumentation has been submitted by the sponsor to justify the assumption that aztreonam lysinate might be of potential significant benefit for the treatment of gram negative bacterial lung infection in cystic fibrosis. The assumption of benefit will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Aztreonam lysinate is a synthetic antibiotic with activity against a wide range of gram-negative bacteria including Pseudomonas aeruginosa. The sponsor has developed a formulation for dry powder inhalation to be administered with a commercial device. It acts by disrupting protein synthesis (the building up) of the bacterial cell wall and this kills the microorganisms.

The effects of aztreonam lysinate were evaluated in experimental models.

At the time of submission of the application for orphan designation, clinical trials in patients with treatment of gram negative bacterial lung infection in cystic fibrosis were ongoing.

Aztreonam lysinate was not marketed anywhere worldwide for treatment of gram negative bacterial lung infection in 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 a positive opinion on 14 May 2004 recommending the granting of the above-mentioned designation.

Update: Aztreonam lysinate (inhalation use) (Cayston) has been authorised in the EU since 21 September 2009 for the suppressive therapy of chronic pulmonary infections due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF) aged 18 years and older. The primary support for this indication is based on two single 28-day course placebo-controlled studies. The data to support the sustainability of the observed short term benefit over subsequent courses of treatment are limited. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

• 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.