EU/3/05/325

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Orphan designation

On 7 November 2005, orphan designation (EU/3/05/325) was granted by the European Commission to Stricent AB, Sweden, for mannitolum for the treatment of cystic fibrosis.

The sponsorship was transferred to Pharmaxis UK Limited, United Kingdom, in October 2006. The sponsor subsequently changed name to Pharmaxis Pharmaceuticals Limited in May 2008.

For a list of the administrative updates to this public summary of opinion please refer to the PDF document below.

What is 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.

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

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).

What treatments are available?

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.

How is this medicine expected to work?

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.

What is the stage of development of this medicine?

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.

Opinions on orphan medicinal products designations are based on the following cumulative criteria:
  • 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.

Key facts

Product details for <p>Mannitolum</p>
Active substanceMannitolum
Medicine NameBronchitol
Disease/conditionTreatment of cystic fibrosis
Date of decision07/11/2005
OutcomePositive
Orphan decision numberEU/3/05/325

Review of designation

During its meeting of 8-9 November 2011, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/05/325 for Bronchitol (mannitol, previously known as mannitolum) 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 satisfactory 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 maintained.

Life-threatening or long-term debilitating nature of the condition

The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Bronchitol for 'treatment of cystic fibrosis in adults aged 18 years and above as an add-on therapy to best standard of care'.

This falls within the scope of the product’s designated orphan indication, 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 2005. Cystic fibrosis remains a condition that is debilitating in the long term and life-threatening, particularly due to respiratory insufficiency resulting from long-term lung infection.

Prevalence of the condition

The sponsor provided updated information on the prevalence of cystic fibrosis based on published literature and recent data from national registries.

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 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 methods were authorised in the EU for the treatment of cystic fibrosis. To treat the lung disease component of cystic fibrosis, mucolytics such as rhDNase and acetylcysteine were used to dissolve the secretions and facilitate the clearance of bronchial mucus, leading to a reduction of lung infections and inflammation.

Significant benefit over existing treatments

The COMP noted that Bronchitol is an osmotic agent that works in a different way to authorised medicines to facilitate mucus clearance. It also noted that in a main study of cystic-fibrosis patients, some of whom were taking rhDNase, Bronchitol showed a small but significant improvement in patients’ forced expiratory volume in one second (FEV1) as well as a modest reduction in exacerbations. The COMP concluded that the claim of significant benefit is justified on the basis of its mechanism of action and added efficacy when used in addition to currently used treatments such as rhDNase.

Therefore, although other satisfactory methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Bronchitol is of significant benefit for patients affected by cystic fibrosis.

Conclusions

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

Related information

Sponsor’s contact details:

Pharmaxis Pharmaceuticals Limited
The Priory
Stomp Road
Burnham
Buckinghamshire
SL1 7LW
United Kingdom
Tel. +44 (0)1628 902121
Fax +44 (0)1628 669355
E-mail: info@pharmaxis.com.au

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.